"Niacin" redirects here. For the neo-fusion band, see Niacin (band) .
Niacin (also known as vitamin B3 , nicotinic acid and vitamin PP ) is an organic compound with the chemical formula|formula chem|C|6|H|5|NO|2 and, depending on the definition used, one of the forty to eighty essential nutrient|essential human nutrients .
Niacin is one of five vitamins (when lacking in human diet) associated with a pandemic Nutrition disorder|deficiency disease : niacin deficiency ( pellagra ), vitamin C deficiency ( scurvy ), thiamin deficiency ( beriberi ), vitamin D deficiency ( rickets ), vitamin A deficiency ( night blindness and other symptoms). Niacin has been used for over 50 years to increase levels of High-density lipoprotein|HDL in the blood and has been found to modestly decrease the risk of cardiovascular events in a number of controlled human trials.
This colorless, water-soluble solid is a derivative of pyridine , with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide , nicotinamide ("niacinamide"), where the carboxyl group has been replaced by a carboxamide group (chem|CONH|2), as well as more complex amides and a variety of esters. The terms niacin, nicotinamide, and vitamin B3 are often used interchangeably to refer to any member of this family of compounds, since they have similar biochemical activity.
Niacin cannot be directly converted to nicotinamide, but both compounds could be converted to Nicotinamide adenine dinucleotide|NAD and NADP in vivo . Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects (lipid modifying effects) as niacin. Nicotinamide does not reduce cholesterol or cause flushing (physiology)|flushing .cite journal |author=Jaconello P |title=Niacin versus niacinamide |journal=CMAJ |volume=147 |issue=7 |pages=990 |year=1992 |month=October |pmid=1393911 |pmc=1336277 Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.cite journal |author=Knip M, Douek IF, Moore WP, et al. |title=Safety of high-dose nicotinamide: a review |journal=Diabetologia |volume=43 |issue=11 |pages=1337–45 |year=2000 |pmid=11126400 | doi = 10.1007/s001250051536 Niacin is a precursor to Nicotinamide adenine dinucleotide|NAD+/NADH and NADPH|NADP+/NADPH , which play essential metabolism|metabolic roles in living cell s.cite book |author=Cox, Michael; Lehninger, Albert L; Nelson, David R. |title=Lehninger principles of biochemistry |publisher=Worth Publishers |location=New York |year=2000 |isbn=1-57259-153-6 Niacin is involved in both DNA repair, and the production of steroid hormone s in the adrenal gland .
Dietary needs
One recommended daily allowance of niacin is 2–12& nbsp;mg/day for children, 14& nbsp;mg/day for women, 16& nbsp;mg/day for men, and 18& nbsp;mg/day for pregnant or breast-feeding women.cite web | url = http://lpi.oregonstate.edu/infocenter/vitamins/niacin/ | title = Niacin | publisher = Linus Pauling Institute | year = 2007 | last = Jacobson | first = EL | accessdate = 2011-08-08 The upper limit for adult men and women is 35& nbsp;mg/day, which is based on Flushing (physiology)|flushing as the critical adverse effect.Citation needed|reason=reliable source needed |date=August 2011In general, niacin status is tested through urinary biomarker s,cite book |author=Institute of Medicine |authorlink=Institute of Medicine |title=Dietary Reference Intakes Research Synthesis: Workshop Summary |publisher=National Academies Press |year=2006 |page=37 |url= http://books.nap.edu/openbook.php? record_id=11767& page=37 which are believed to be more reliable than plasma levels.cite journal |author=Jacob RA, Swendseid ME, McKee RW, Fu CS, Clemens RA |title=Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites |journal=J. Nutr. |volume=119 |issue=4 |pages=591–8 |year=1989 |month=April |pmid=2522982 |url= http://jn.nutrition.org/cgi/pmidlookup? view=long& pmid=2522982
Deficiency
Main|Pellagra At present, niacin deficiency is sometimes seen in developed countries, and it is usually apparent in conditions of poverty, malnutrition, and chronic alcoholism.cite journal |author=Pitsavas S, Andreou C, Bascialla F, Bozikas VP, Karavatos A |title=Pellagra encephalopathy following B-complex vitamin treatment without niacin |journal=Int J Psychiatry Med |volume=34 |issue=1 |pages=91–5 |year=2004 |pmid=15242145 |url= http://baywood.metapress.com/link.asp? id=29xv1gg1u17krgjh It also tends to occur in areas where people eat maize (corn, the only grain low in digestible niacin) as a staple food. A special cooking technique called nixtamalization is needed to increase the bioavailability of niacin during maize meal/flour production.
Mild niacin deficiency has been shown to slow metabolism, causing decreased tolerance to cold.
Severe deficiency of niacin in the diet causes the disease pellagra , which is characterized by diarrhea, dermatitis, and dementia, as well as “necklace” lesions on the lower neck, hyperpigmentation, thickening of the skin, inflammation of the mouth and tongue, digestive disturbances, amnesia, delirium, and eventually death, if left untreated.cite journal|title=Rapid resolution of delusional parasitosis in pellagra with niacin augmentation therapy|journal=General Hospital Psychiatry|first=Ravi|last=Prakash|coauthors=Sachin Gandotra, Lokesh Kumar Singh, Basudeb Das, Anuja Lakra|volume=30|issue=6|pages=581–4|doi= 10.1016/j.genhosppsych.2008.04.011|url= http://www.sciencedirect.com/science/article/B6T70-4T24FKB-D/2/f619871a3d1f1d626b775c84523d6d94|pmid=19061687|year=2008 Common psychiatric symptoms of niacin deficiency include irritability, poor concentration, anxiety, fatigue, restlessness, apathy, and depression. Studies have indicated that, in patients with alcoholic pellagra, niacin deficiency may be an important factor influencing both the onset and severity of this condition. Alcoholic patients typically experience increased intestinal permeability, leading to negative health outcomes.
Hartnup’s disease is a hereditary nutritional disorder resulting in niacin deficiency. This condition was first identified in the 1950s by the Hartnup family in London. It is due to a deficit in the intestines and kidneys, making it difficult for the body to break down and absorb dietary tryptophan . The resulting condition is similar to pellagra, including symptoms of red, scaly rash, and sensitivity to sunlight. Oral niacin is given as a treatment for this condition in doses ranging from 40–200& nbsp;mg, with a good prognosis if identified and treated early. Niacin synthesis is also deficient in carcinoid syndrome , because of metabolic diversion of its precursor tryptophan to form serotonin .
Lipid-modifying effects
Niacin binds to and stimulates a G-protein-coupled receptor , GPR109A , which causes the inhibition of fat breakdown in adipose tissue.cite journal |author=Gille A, Bodor ET, Ahmed K, Offermanns S |title=Nicotinic acid: pharmacological effects and mechanism of action |journal=Annu Rev Pharmacol Toxicol |volume=48 |pages=79-106 |year=2008|pmid=17705685 |doi=. Nicotinamide does not bind this receptor which explains why it does not affect blood lipid levels. Lipids that are liberated from adipose tissue are normally used to build very-low-density lipoprotein s (VLDL) in the liver, which are precursors of low-density lipoprotein (LDL) or "bad" cholesterol. Because niacin blocks the breakdown of fats, it causes a decrease in free fatty acid s in the blood and, as a consequence, decreases the secretion of VLDL and cholesterol by the liver.cite book |author=Katzung, Bertram G. |title=Basic and clinical pharmacology |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2006 |isbn=0071451536 |url= http://www.medicinenet.com/niacin/article.htm
By lowering VLDL levels, niacin also increases the level of high-density lipoprotein (HDL) or "good" cholesterol in blood, and therefore it is sometimes prescribed for people with low HDL, who are also at high risk of a heart attack.cite journal |author=McGovern ME |title=Taking aim at HDL-C. Raising levels to reduce cardiovascular risk |journal=Postgrad Med |volume=117 |issue=4 |pages=29–30, 33–5, 39 passim |year=2005 |pmid=15842130 |doi=cite journal |author=Canner PL, Berge KG, Wenger NK, et al. |title=Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin |journal=J. Am. Coll. Cardiol. |volume=8 |issue=6 |pages=1245–55 |year=1986 |pmid=3782631 |doi=10.1016/S0735-1097(86)80293-5
The ARBITER 6-HALTS study, reported at the 2009 annual meeting of the American Heart Association and in the New England Journal of Medicinecite journal |author=Taylor AJ, Villines TC, Stanek EJ, et al. |title=Extended-release niacin or ezetimibe and carotid intima-media thickness |journal=N. Engl. J. Med. |volume=361 |issue=22 |pages=2113–22 |year=2009 |month=November |pmid=19915217 |doi=10.1056/NEJMoa0907569 concluded that, when added to statins , 2000& nbsp;mg/day of slow-release niacin was more effective than ezetimibe (Zetia) in reducing Intima-media thickness#IMT measurements in the carotid artery|carotid intima-media thickness , a marker of atherosclerosis.cite news|title=Study Raises Questions About Cholesterol Drug’s Benefit|first=Natasha|last=Singer|date=November 15, 2009|accessdate=November 16, 2009|newspaper= The New York Times |url= http://www.nytimes.com/2009/11/16/health/research/16heart.html Additionally, a recent meta-analysis covering 11 randomized controlled clinical trials found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution.cite journal|pmid=20079494|year=2010|last1=Bruckert|first1=E|last2=Labreuche|first2=J|last3=Amarenco|first3=P|title=Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis|volume=210|issue=2|pages=353–61|doi=10.1016/j.atherosclerosis.2009.12.023|journal=Atherosclerosis
However, a 2011 study ( AIM-HIGH ) was halted early because patients showed no decrease in cardiovascular events, but did experience an increase in the risk of stroke. These patients already had LDL levels well-controlled by a statin drug, and the aim of the study was to evaluate slow-release niacin (2000& nbsp;mg per day) to see if raising HDL levels had an additional positive effect on risk. In this study, it did not have such an effect, and appeared to increase stroke risk. http://www.npr.org/blogs/health/2011/05/28/136678665/study-boosting-good-cholesterol-with-niacin-did-not-cut-heart-risks? ps=sh_sthdl The role of niacin in patients whose LDL is not well-controlled (as in the majority of previous studies with niacin) is still under study and debate. However, it does not seem to offer benefits via raising HDL, in patients already lowering LDL by taking a statin.
Toxicity
Pharmacological doses of niacin (1.5 - 6 g per day) occasionally lead to side effects that can include dermatological conditions such as Flushing (physiology)|skin flushing and itching, dry skin, and skin rashes including eczema exacerbation and acanthosis nigricans . Some of these symptoms are generally related to niacin's role as the rate limiting cofactor in the histidine decarboxylase enzyme which converts l-histidine into histamine.Citation needed|reason=histidine decarboxylase is B6-dependent, not B3-dependent|date=May 2011 H1 and H2 receptor mediated histamine is metabolized via a sequence of mono (or di-) amine oxidase and COMT into methylhistamine which is then conjugated through the liver's CYP450 pathways. Persistent flushing and other symptoms may indicate deficiencies in one or more of the cofactors responsible for this enzymatic cascade. Gastrointestinal complaints, such as dyspepsia (indigestion), nausea and liver toxicity fulminant hepatic failure , have also been reported. Side effects of hyperglycemia , cardiac arrhythmias and "birth defects in experimental animals" have also been reported.cite book |author=Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2006 |isbn=0071422803
Flushing lasts for about 15 to 30 minutes, and is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing. This effect is mediated by GPR109A -mediated prostaglandin release from the Langerhans cells of the skin and can be blocked by taking 300& nbsp;mg of aspirin half an hour before taking niacin, by taking one tablet of ibuprofen per day or by co-administering the prostaglandin receptor antagonist laropiprant . Taking the niacin with meals also helps reduce this side effect. After several weeks of a consistent dose, most patients no longer flush.cite web | title = Guidelines for Niacin Therapy For the Treatment of Elevated Lipoprotein a (Lpa) | publisher = Rush University Medical Center|Rush Hemophilia & Thrombophilia Center | url = http://www.rush.edu/Rush_Document/Niacin%20therapy%20for%20elevated%20Lpa,0.pdf | quote = facial flushing is a common side effect of niacin therapy that usually subsides after several weeks of consistent niacin use | date = August 15, 2002, Revised July 27, 2005 | accessdate = 20 November 2009 Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.cite book |author=Katzung, Bertram G. |title=Basic and clinical pharmacology |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2006 |isbn=0071451536 cite journal | title = Options for therapeutic intervention: How effective are the different agents? | journal = European Heart Journal Supplements | volume = 8 | pages = F47–F53 | doi = 10.1093/eurheartj/sul041 | accessdate = 2008-03-31 | last = Barter | first = P | year = 2006 | issue = F One study showed the incidence of flushing was significantly lower with a sustained release formulationcite journal |author=Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C |title=Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C |journal=Curr Med Res Opin |volume=20 |issue=8 |pages=1253–68 |year=2004 |pmid=15324528 |doi=10.1185/030079904125004402 though doses above 2 g per day have been associated with hepatotoxicity|liver damage , in particular, with slow-release formulations. Flushing is often thought to involve histamine, but histamine has been shown not to be involved in the reaction.cite journal | title = Niacin-induced "Flush" Involves Release of Prostaglandin D2 from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model |year=December 2008 |author=Papaliodis D, Boucher W, Kempuraj D, Michaelian M, Wolfberg A, House M, Theoharides TC |journal=J Pharmacol Exp Ther |volume=327 |issue=3 |pages=665–72 |pmid=18784348 |url= http://jpet.aspetjournals.org/cgi/pmidlookup? view=long& pmid=18784348 | doi = 10.1124/jpet.108.141333 Prostaglandin ( PGD2|PGD2 ) is the primary cause of the flushing reaction, with serotonin appearing to have a secondary role in this reaction.
Although high doses of niacin may elevate blood sugar , thereby worsening diabetes mellitus , recent studies show the actual effect on blood sugar to be only 5–10%. Patients with diabetes who continued to take anti-diabetes drugs containing niacin did not experience major blood glucose changes. Thus looking at the big picture, niacin continues to be recommended as a drug for preventing CVD in patients with diabetes.
Hyperuricemia is another side effect of taking high-dose niacin, and may exacerbate gout .cite journal |author=Capuzzi DM, Morgan JM, Brusco OA, Intenzo CM |title=Niacin dosing: relationship to benefits and adverse effects |journal=Curr Atheroscler Rep |volume=2 |issue=1 |pages=64–71 |year=2000 |pmid=11122726| doi = 10.1007/s11883-000-0096-y
Niacin in doses used to lower cholesterol levels has been associated with birth defect s in laboratory animals, with possible consequences for infant development in Pregnancy|pregnant women.
Niacin, particularly the time-release variety, at extremely high doses can cause acute toxic reactions.cite journal |author=Mittal MK, Florin T, Perrone J, Delgado JH, Osterhoudt KC |title=Toxicity from the use of niacin to beat urine drug screening |journal=Ann Emerg Med |volume=50 |issue=5 |pages=587–90 |year=2007 |pmid=17418450 |doi=10.1016/j.annemergmed.2007.01.014 Extremely high doses of niacin can also cause niacin maculopathy , a thickening of the macula and retina , which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases.cite journal |author=Gass JD |title=Nicotinic acid maculopathy. 1973 |journal=Retina (Philadelphia, Pa.) |volume=23 |issue=6 Suppl |pages=500–10 |year=2003 |pmid=15035390 |doi=
Inositol hexanicotinate
One form of dietary supplement is inositol hexanicotinate (IHN), which is inositol that has been ester ified with niacin on all six of inositol's alcohol groups. IHN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, or 1000& nbsp;mg/tablets or capsules. It is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting the active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, the evidence that it has lipid-modifying functions is contradictory, at best. As the clinical trials date from the early 1960s (Dorner, Welsh) or the late 1970s (Ziliotto, Kruse, Agusti), it is difficult to assess them by today's standards.cite web | url = http://www.medscape.com/viewarticle/447528 | title = No-Flush Niacin for the Treatment of Hyperlipidemia | last = Taheri | first = R | publisher = Medscape | date = 2003-01-15 | accessdate = 2008-03-31 One of the last of those studies affirmed the superiority of inositol and xantinol esters of nicotinic acid for reducing serum free fatty acid,cite journal | author=Kruse W, Kruse W, Raetzer H, Heuck CC, Oster P, Schellenberg B, Schlierf G | title=Nocturnal inhibition of lipolysis in man by nicotinic acid and derivatives | journal=European Journal of Clinical Pharmacology | volume=16 | issue=1 | year=1979 | pages=11–15 | pmid=499296 | doi=10.1007/BF00644960 but other studies conducted during the same period found no benefit.cite journal | author=Meyers CD, Carr MC, Park S, Brunzell JD | title=Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia | journal=Annals of Internal Medicine | volume=139 | issue=12 | year=2003 | pages=996–1002 | url = http://www.annals.org/content/139/12/996.full.pdf+html | pmid=14678919 Studies explain that this is primarily because "flush-free" preparations do not contain any free nicotinic acid. A more recent placebo-controlled trial was small (n=11/group), but results after three months at 1500& nbsp;mg/day showed no trend for improvements in total cholesterol, LDL-C, HDL-C or triglycerides.cite journal | author=Benjó AM, Maranhão RC, Coimbra SR, Andrade AC, Favarato D, Molina MS, Brandizzi LI, da Luz PL | title=Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment | journal=Atherosclerosis | volume=187 | issue=1 | year=2006 | pages=116–122 | pmid=16458316 | doi=10.1016/j.atherosclerosis.2005.08.025 Thus, so far there is not enough evidence to recommend IHN to treat dyslipidemia . Furthermore, the American Heart Association and the National Cholesterol Education Program both take the position that only prescription niacin should be used to treat dyslipidemias, and only under the management of a physician. The reason given is that niacin at effective intakes of 1500–3000& nbsp;mg/day can also potentially have severe adverse effects. Thus liver function tests to monitor liver enzymes are necessary when taking therapeutic doses of niacin, including alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT).
Biosynthesis and chemical synthesis
The liver can synthesize niacin from the essential amino acid tryptophan , requiring 60 Gram#SI_multiples|mg of tryptophan to make one mg of niacin.cite web | url = http://lpi.oregonstate.edu/infocenter/vitamins/niacin/ | title = Niacin | publisher = Linus Pauling Institute | year = 2007 | last = Jacobson | first = EL | accessdate = 2008-03-31 The 5-membered aromatic heterocyclic compound|heterocycle of tryptophan is cleaved and rearranged with the amino acid|alpha amino group of tryptophan into the 6-membered aromatic heterocycle of niacin. Riboflavin , Vitamin B6 and iron are required in some of the reactions involved in the conversion of tryptophan to NAD.
Several million kilograms of niacin are manufactured each year, starting from 3-Methylpyridine|3-methylpyridine .
Receptor
In addition to its effects as NAD and NADP, niacin may have additional effects by receptor activation . The receptor for niacin is a G protein-coupled receptor called HM74A.cite journal |author=Zhang Y, Schmidt RJ, Foxworthy P, et al. |title=Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A |journal=Biochem. Biophys. Res. Commun. |volume=334 |issue=2 |pages=729–32 |year=2005 |pmid=16018973 |doi=10.1016/j.bbrc.2005.06.141 It couples to the Gi alpha subunit .cite journal |author=Zellner C, Pullinger CR, Aouizerat BE, et al. |title=Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors |journal=Hum. Mutat. |volume=25 |issue=1 |pages=18–21 |year=2005 |pmid=15580557 |doi=10.1002/humu.20121
Food sources
Niacin is found in variety of foods, including liver, chicken, beef, fish, cereal, peanuts and legumes, and is also synthesized from tryptophan , which is found in meat, dairy and eggs.
Animal products:
liver , heart and kidney
chicken (food)|chicken
beef
fish (food)|fish : tuna , salmon
egg (food)|eggs
Fruits and vegetables:
avocado s
date palm|date s
tomato es
leaf vegetable s
broccoli
carrot s
sweet potato es
asparagus
Seeds:
nut (fruit)|nut s
whole grain Product (business)|product s
legume s
saltbush seeds
Fungi:
mushroom s
brewer's yeast
Other:
Vegemite (from spent brewer's yeast)
History
Niacin was first described by Austrian chemist Hugo Weidel in 1873 in his studies of nicotine .cite journal | first = H | last = Weidel | title = Zur Kenntniss des Nicotins | journal = Justus Liebig's Annalen der Chemie und Pharmacie | year = 1873 | volume = 165 | pages = 330–349 | doi = 10.1002/jlac.18731650212 | issue = 2 The original preparation remains useful: The oxidation of nicotine using nitric acid .OrgSynth | author = Samuel M. McElvain | title = Nicotinic Acid | collvol = 1 | collvolpages = 385| year = 1941 | prep = CV1P0385.pdf Niacin was extracted from livers by Norweigan biochemist Conrad Elvehjem , who later identified the active ingredient, then referred to as the "pellagra-preventing factor" and the "anti-blacktongue factor."cite journal |author=Elvehjem CA, Madden RJ, Strongandd FM, Woolley DW |year=1938 |title=The isolation and identification of the anti-blacktongue factor J |journal = J. Biol. Chem. |volume=123 |pages=137–149 |url= http://www.jbc.org/content/123/1/137.full.pdf |format=PDF When the biological significance of nicotinic acid was realized, it was thought appropriate to choose a name to dissociate it from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name 'niacin' was derived from ni cotinic ac id + vitam in.
Carpenter found in 1951 that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11.cite journal |author=LAGUNA J, CARPENTER KJ |title=Raw versus processed corn in niacin-deficient diets |journal=J. Nutr. |volume=45 |issue=1 |pages=21–8 |year=1951 |month=September |pmid=14880960 |url= http://jn.nutrition.org/cgi/pmidlookup? view=long& pmid=14880960 This process, known as nixtamalization , was discovered by the prehistoric civilizations of Mesoamerica.cite web | url = http://www.umm.edu/altmed/articles/vitamin-b3-000335.htm | title = Vitamin B3 | publisher = University of Maryland, College Park|University of Maryland Medical Center | date = 2002-01-04 | accessdate = 2008-03-31
Niacin is referred to as vitamin B3 because it was the third of the B vitamins to be discovered. It has historically been referred to as "vitamin PP" or "vitamin P-P".
Research
as of|August 2008, a combination of niacin with laropiprant is being tested in a clinical trial. Laropiprant reduces facial flushes induced by niacin.cite journal |author=Paolini JF, Bays HE, Ballantyne CM, et al. |title=Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors |journal=Cardiol Clin |volume=26 |issue=4 |pages=547–60 |date=November 2008 |doi=10.1016/j.ccl.2008.06.007 |pmid=19031552
