Lactulose

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Lactulose
Lactulose2.png
Lactulose ball-and-stick.png
Systematic (IUPAC) name
4-O-β-D-Galactopyranosyl-β-D-fructofuranose
OR
(2S,3R,4S,5R,6R)-2-((2R,3S,4S,5R)-4,5-dihydroxy-2,5-bis(hydroxymethyl) tetrahydrofuran-3-yloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Clinical data
Trade names Constulose
AHFS/Drugs.com monograph
MedlinePlus a682338
Pregnancy cat. B (US)
Legal status P (UK)
Routes Oral
Pharmacokinetic data
Bioavailability Poorly absorbed
Metabolism 100% in colon by enteric bacteria
Half-life 1.7-2 hours
Excretion Fecal
Identifiers
CAS number 4618-18-2 YesY
ATC code A06AD11
PubChem CID 11333
DrugBank DB00581
ChemSpider 10856 YesY
UNII 9U7D5QH5AE YesY
KEGG D00352 YesY
ChEBI CHEBI:6359 YesY
ChEMBL CHEMBL296306 YesY
Chemical data
Formula C12H22O11 
Mol. mass 342.296 g/mol
 YesY (what is this?)  (verify)

Lactulose /ˈlæktlz/ is a synthetic, non-digestible sugar used in the treatment of chronic constipation[1] and hepatic encephalopathy, a complication of liver disease. It is a disaccharide (double-sugar) formed from one molecule each of the simple sugars (monosaccharides) fructose and galactose. It is produced commercially by isomerization of lactose.

It is broadly classified as an osmotic laxative.

Medical Application[edit]

Constipation[edit]

Lactulose is used in the treatment of chronic constipation.[2] in patients of all ages as a long-term treatment. Its dosage is adjusted depending on the constipation severity and desired effect, from stool softening to a strong bowel movement. Dosage is reduced in case of galactosemia as most preparation contain the monosaccharide galactose due to its synthesis process.

This disaccharide is not absorbed in the intestine nor broken down by human enzymes, and thus stays in the digestive bolus through most of its course, causing retention of water through osmosis leading to softer, easier to pass stool. It has a secondary laxative effect in the colon, where it is fermented by the gut flora, producing metabolites which have osmotic powers and peristalsis-stimulating effects (such as acetate), but also methane involved in flatulence.

Lactulose is notably indicated in treating patients with chronic constipation due to forgetting or ignoring the need for defecation, including children and elderly patients, as it may be added to beverages without altering the taste, and also it can be administered at a low dosage, gradually increasing over time until the bowel movement becomes strong enough that it cannot be avoided.

Lactulose may be used to counter the constipating effects of opioids, and in the symptomatic treatment of hemorrhoids as a stool softener.

Lactulose is considered a prebiotic because it modulates the beneficial bacterial flora of the gut and is considered a digestive aid. Modulation of gut flora presumably works by reducing potential pathogenic bacteria such as Escherichia coli and Staphylococcus species in stool, and increases non-urease producing Lactobacillus, thereby limiting ammonia production. Moreover, lactulose is converted to lactic and acetic acid which results in acidification of colonic contents. The low pH decreases passive non-ionic diffusion of ammonia thus lowering its systemic concentration. Furthermore, with its prebiotic potential, lactulose also encourages growth of probiotic bacteria such as Bifidobacterium species that are known to have health-promoting effects.[3]:668−669

Lactulose is sold as an over-the-counter laxative in most countries in the world,with the notable exception of the United States and Austria where it requires a prescription, mainly on the unfounded fear that it could be harmful to diabetics.[citation needed]

Hepatic encephalopathy[edit]

Lactulose is useful in treating the hyperammonemia caused by hepatic encephalopathy, because it helps "draw out" ammonia (NH3) from the body. It is useful for preventing hyperammonemia caused as a side effect of administration of Depakote.[4]

Lactulose is metabolized in the colon by bacterial flora to short chain fatty acids including the production of the lactic acid and acetic acid. This partially dissociates, acidifying the colonic contents (increasing the H+ concentration in the gut).[5] This favors the formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and effectively reducing plasma NH3 concentrations.

The effectiveness of lactulose in treating hepatic encephalopathy is somewhat controversial.[6][7] However, lactulose can effectively be used as secondary prophylaxis of hepatic encephalopathy in patients with cirrhosis.[8] Moreover, recent studies showed improved cognitive functions of cirrhotic patients with minimal hepatic encephalopathy treated with lactulose.[9]

Lactulose is not absorbed, does not affect the absorption of spironolactone and may be used by diabetics. It is used in patients with cirrhosis/hepatic encephalopathy to limit the proliferation of ammonia-forming gut organisms and increase the clearance of protein load in the gut.

Lactulose for hepatic encephalopathy generally requires oral dosage of at least three tablespoons (45 ml) three or four times a day with episodic diarrhea and constant flatulence almost a certain side effect. People who take lactulose at this level of dosage generally end up wearing an adult diaper and plastic pants for any activities away from home or at night (with a chux pad for the bed) because the diarrhea can occur swiftly and without much warning.

Lactulose Breath Test[edit]

Lactulose is used as a test of small intestine bacterial overgrowth (SIBO). Recently the reliability of it for diagnosing SIBO has been seriously questioned.[10][11][12][13] A large amount of it is given with subsequent testing of molecular hydrogen gas in the breath. The test is positive if an increase in exhaled hydrogen occurs before that which would be expected by normal colonocyte digestion. An earlier result has been hypothesized to indicate digestion occurring within the small intestine. An alternate explanation for differences in results is the variance in small bowel transit time among tested subjects.[13]

Food Applications[edit]

Lactulose is also a food ingredient, better known as galactofructose, with sweet taste and offering beneficial health benefits on digestive health. Galactofructose is a milk-derived disaccharide obtained by a simple isomerisation of lactose. It is recognized for its digestive qualities by the EFSA (European Food Safety Authorities) and KFDA (Korean Food & Drug Administration). Its bifidogenic property was first identified for infant food formulas, already in 1957 when the growth of the bifidogenic bacteria in infants by adding galactofructose to their diet was studied.[1] Two years later it was also shown to be effective to regulate transit disorders through its osmotic effect.

Health Benefits[edit]

Transit effect[edit]

Galactofructose provides a more comfortable transit on healthy people. This results from the combination of different effects, at different levels of the intestinal tract. Before galactofructose is used by the intestinal bacteria, it exerts an osmotic action in the small intestine. It draws water into the intestinal lumen, thereby increasing the mass of the stool. This in turn has a stimulating effect on the intestinal musculature and stimulates the bowel movement. In addition, in the colon, total biomass, stool volume and osmotic pressure is increased and pH decreased, resulting in accelerated bowel movement and shorter transit time.[14][15]

A regular daily consumption of galactofructose optimizes functioning of the intestinal tract by regulating intestinal transit.[medical citation needed] Some factors in diet and lifestyle lead to small intestinal disorders, such as occasional constipation states. Slow gut transit time causes discomfort and has been proposed as a promoting factor to the accumulation of toxic substances in the organism. Regulation of the intestinal transit time, especially in people with slow transit, improves overall well – being and quality of life. Lactulose accelerates small bowel transit.

The daily dose recommended by the authorities is 10g (15 ml. of syrup) per day.[16] Very few side effects are observed. Transit effect of galactofructose does not affect gastric emptying nor protein and lipid metabolism.[17]

Bifidogenic/prebiotic effect[edit]

Galactofructose is obtained from the milk sugar lactose by isomerisation of glucose to fructose, and consists of galactose linked by ß-1,4-linkage to fructose. It is not defined as a fibre in Europe because of its low degree of polymerization (DP2). However, it holds many of the health benefits attached to fibres as the ß-1,4-linkage between galactose and fructose cannot be degraded by animal or human digestive enzymes.

As a result it remains undigested until it reaches the large intestine. In the colon, galactofructose is the energy source for beneficial saccharolytical bacteria like Bifidobacteria and Lactobacilli which can metabolise it to produce short-chain fatty acids.[18] Galactofructose acts as a prebiotic within the colonic microflora, increasing numbers of bifidobacteria and improving transit time in healthy volunteers: it is the bifidogenic effect.

A number of human intervention studies have confirmed the bifidogenic nature of galactofructose in healthy consumers.[19] For instance, in a 14 day(s) intervention study it stimulated bifidobacterial growth at a dose of 3g/day. Conversely, the numbers of non-beneficial bacteria Clostridium perfringens, Streptococcus spp, Bacteroides spp, and the Enterobacteriaceae decreased significantly.

This bifidogenic effect initiates a number of gastrointestinal and systemic health benefits that may be associated to a strengthened immune system, improved intestinal barrier function and reduced susceptibility to illness.

Other benefits[edit]

The health effects of galactofructose are not limited to gut health as it can also be used to stimulate calcium and magnesium absorption. Clinical trials conducted in 24 healthy adult volunteers have shown that when ingesting food containing 4g of galactofructose, 300 mg calcium and 150 mg magnesium the absorption of calcium and magnesium is enhanced.

A recent study has also revealed the beneficial effect of galactofructose on insulin resistance through stimulation of colonic fermentation which reduced lipotoxicity.

Finally, scientific results support the idea that modulating gut microbiota could be beneficial for managing weight issues and obesity. Prebiotics and galactofructose in particular seem efficient at modifying gut microflora and potentially achieving these effects.

Applications[edit]

Galactofructose is commercially available either in liquid form as a yellowish, odourless clear syrup, or in solid form as an amorphous white powder, which is highly soluble in water. It exhibits a sweetness which is equivalent to 60% to 80% of the sweetness of sucrose, and is very stable at both high temperature and low pH conditions.

A series of tests also have been performed on yogurts, drink yogurts, multi-juice drinks and bakery products including cereal bars, breakfast cereals, biscuits and even ice cream to study the behaviour of galactofructose during processing and its effect on sensory properties. In every application it was shown to process well due to the solubility of the powder and the well-balanced viscosity of the syrup.[20][full citation needed]

The presence of galactofructose has no major effect on sensory properties, colour and texture, so manufacturers can also consider incorporating it in other applications such as beverages, fruit preparations or in preparations for infants.

Side effects[edit]

When used at low dosage and as a food additive, galactofructose is known for its good acceptance, with limited side effects, similar to many food products.

At higher dosage, in pharmaceutical usage, common side effects of lactulose are abdominal cramping, borborygmus, gas and pungent, noisy flatulence that some people find difficult to control in social situations. In normal individuals, overdose is considered uncomfortable, but not life threatening.[21] Uncommon normal side effects are nausea and vomiting.

In sensitive individuals, such as the elderly or people with reduced kidney function, excess lactulose dosage can result in dehydration and electrolytic disturbances such as high sodium levels.

Lactulose is a nondigestible sugar and contains only about one calorie per millitre.

Although lactulose has less potential to cause dental caries than sucrose, there is a minimal potential because it is a sugar. This should be taken into consideration when taken by people with a high susceptibility to this condition.

References[edit]

  1. ^ Voskuijl W, de Lorijn F, Verwijs W, Hogeman P, Heijmans J, Mäkel W, Taminiau J, Benninga M (November 2004). "PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial". Gut 53 (11): 1590–4. doi:10.1136/gut.2004.043620. PMC 1774276. PMID 15479678. 
  2. ^ Lactulose, MedlinePlus Drug Information
  3. ^ Shukla S, Shukla A, Mehboob S, Guha S (March 2011). "Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy". Aliment. Pharmacol. Ther. 33 (6): 662–71. doi:10.1111/j.1365-2036.2010.04574.x. PMID 21251030. 
  4. ^ Gerstner, T.; Buesing, D.; Longin, E.; Bendl, C.; Wenzel, D.; Scheid, B.; Goetze, G.; Macke, A.; Lippert, G.; Klostermann, W.; Mayer, G.; Augspach-Hofmann, R.; Fitzek, S.; Haensch, C. A.; Reuland, M.; Koenig, S. A. (2006). "Valproic acid induced encephalopathy – 19 new cases in Germany from 1994 to 2003 – A side effect associated to VPA-therapy not only in young children". Seizure 15 (6): 443–448. doi:10.1016/j.seizure.2006.05.007. PMID 16787750.  edit
  5. ^ Patil DH, Westaby D, Mahida YR, Palmer KR, Rees R, Clark ML, Dawson AM, Silk DB (March 1987). "Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy". Gut 28 (3): 255–9. doi:10.1136/gut.28.3.255. PMC 1432706. PMID 3570029. 
  6. ^ Als-Nielsen B, Gluud LL, Gluud C (2004). "Nonabsorbable disaccharides for hepatic encephalopathy". In Als-Nielsen, Bodil. Cochrane Database Syst Rev (2): CD003044. doi:10.1002/14651858.CD003044.pub2. PMID 15106187. 
  7. ^ Shawcross DL, Jalan R (July 2004). "Treatment of hepatic encephalopathy: it's not lactulose". BMJ 329 (7457): 112; author reply 112. doi:10.1136/bmj.329.7457.112. PMC 449830. PMID 15242927. 
  8. ^ Sharma BC, Sharma P, Agrawal A, Sarin SK (September 2009). "Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo". Gastroenterology 137 (3): 885–91, 891.e1. doi:10.1053/j.gastro.2009.05.056. PMID 19501587. 
  9. ^ Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (March 2007). "Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy". Hepatology 45 (3): 549–59. doi:10.1002/hep.21533. PMID 17326150. 
  10. ^ Vanner S (April 2008). "The lactulose breath test for diagnosing SIBO in IBS patients: another nail in the coffin". Am. J. Gastroenterol. 103 (4): 964–5. doi:10.1111/j.1572-0241.2008.01798.x. PMID 18371132. 
  11. ^ Barrett JS, Irving PM, Shepherd SJ, Muir JG, Gibson PR (July 2009). "Comparison of the prevalence of fructose and lactose malabsorption across chronic intestinal disorders". Aliment. Pharmacol. Ther. 30 (2): 165–74. doi:10.1111/j.1365-2036.2009.04018.x. PMID 19392860. 
  12. ^ Grover M, Kanazawa M, Palsson OS, Chitkara DK, Gangarosa LM, Drossman DA, Whitehead WE (September 2008). "Small intestinal bacterial overgrowth in irritable bowel syndrome: association with colon motility, bowel symptoms, and psychological distress". Neurogastroenterol. Motil. 20 (9): 998–1008. doi:10.1111/j.1365-2982.2008.01142.x. PMID 18482250. 
  13. ^ a b Yu D, Cheeseman F, Vanner S (March 2011). "Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS". Gut 60 (3): 334–40. doi:10.1136/gut.2009.205476. PMID 21112950. 
  14. ^ Bass P, Dennis S (1981). "The laxative effects of lactulose in normal and constipated subjects". J. Clin. Gastroenterol. 3 Suppl 1: 23–8. doi:10.1097/00004836-198100031-00005. PMID 7035543. 
  15. ^ Geboes KP, Luypaerts A, Rutgeerts P, Verbeke K (October 2003). "Inulin is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time". Aliment. Pharmacol. Ther. 18 (7): 721–9. doi:10.1046/j.1365-2036.2003.01750.x. PMID 14510746. 
  16. ^ EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (December 2010). "Scientific Opinion on the substantiation of health claims related to lactulose and decreasing potentially pathogenic gastro-intestinal microorganisms (ID 806) and reduction in intestinal transit time (ID 807)". EFSA Journal (European Food Safety Authority) 8 (10): 1086. 
  17. ^ Wutzke KD, Heine WE, Plath C, Leitzmann P, Radke M, Mohr C, Richter I, Gülzow HU, Hobusch D (January 1997). "Evaluation of oro-coecal transit time: a comparison of the lactose-[13C, 15N]ureide 13CO2- and the lactulose H2-breath test in humans". Eur J Clin Nutr 51 (1): 11–9. doi:10.1038/sj.ejcn.1600353. PMID 9023461. 
  18. ^ Ballongue J, Schumann C, Quignon P (1997). "Effects of lactulose and lactitol on colonic microflora and enzymatic activity". Scand. J. Gastroenterol. Suppl. 222: 41–4. PMID 9145445. 
  19. ^ Terada A, Hara H, Kataoka M, Mitsuoka T (1992). "Effect of Lactulose on the Composition and Metabolic Activity of the Human Faecal Flora". Microbial Ecology in Health and Disease 5 (1): 43–50. doi:10.3109/08910609209141303. 
  20. ^ Solactis website
  21. ^ http://www.usp.org/pdf/EN/referenceStandards/msds/1356803.pdf

External links[edit]