Lactulose

Lactulose

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 Y
ATC code	A06AD11
PubChem	CID 11333
DrugBank	APRD01063
ChemSpider	10856 Y
UNII	9U7D5QH5AE Y
KEGG	D00352 Y
ChEBI	CHEBI:6359 Y
ChEMBL	CHEMBL296306 Y
Chemical data
Formula	C12H22O11
Mol. mass	342.296 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H22O11/c13-1-4-6(16)7(17)8(18)11(21-4)22-9-5(2-14)23-12(20,3-15)10(9)19/h4-11,13-20H,1-3H2/t4-,5-,6+,7+,8-,9-,10+,11+,12-/m1/s1 Y Key:JCQLYHFGKNRPGE-FCVZTGTOSA-N Y
N (what is this?)  (verify)

Lactulose (/ˈlæktjʉloʊz/) is a synthetic, non-digestible sugar used in the treatment of chronic constipation 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.

Biochemistry

Lactulose is a disaccharide formed by association of fructose and galactose. It is also called galactofructose.

Its chemical formula is 4-O-β-D-Galactopyranosyl-β-D-fructofuranose

It is a milk derived obtained by isomerisation of lactose. So lactulose, or galactofructose, has the same empiric formula (C12H22O11) and molecular weight (342.3) than lactose.

It naturally occurs during standard milk treatment in few quantities.

Medical Application

Constipation

Lactulose is used in the treatment of chronic constipation. The metabolites of lactulose draw water into the bowel, causing a cathartic effect through osmotic action. It is safe for people of all ages, except for those in a very small percentage of the population that are galactose intolerant. Dosage may have to be adjusted over time to produce the desired effect because the laxative effect can decline with daily treatment.

Lactulose works by increasing the water content and volume of the stools in the bowel, making them softer and easier to pass. Lactulose is made up of sugar molecules and is partly broken down by the bacteria that live in the lower part of the gut. This leads to the contents of the gut becoming more acidic because there are carboxylic acids among its metabolites, which are not absorbed from the lower bowel. That in turn causes water to be retained in the lower bowel. This increases the amount of water in the stools, softening them and making them easier to pass. The added volume of gas and flatulence caused by fermentation of the lactulose adds to the volume of the fecal material, and makes it easier to expel. The slightly acidic condition of the colon caused by the presence of acids causes active peristalsis. The combined effect of all of these processes relieves constipation in a very effective manner.

Lactulose is useful in treating people with chronic constipation due to forgetting or ignoring the need for defecation. The treatment is to start the dosage at a low amount and then gradually increase it over a period of weeks until the urgency is such that a daily bowel movement cannot possibly be ignored. After an efficacious dosage is determined, it is maintained indefinitely or increased as needed over time.

Lactulose is useful in treating people who abuse laxatives provided that they use lactulose as their only laxative drug, because it has very low toxicity yet produces powerful results.

Lactulose is useful for negating the constipating effects of opiates and opioids, as in individuals who are on narcotic pain medication, are opioid dependent, or are receiving Opioid Replacement Therapy such as with methadone or buprenorphine for a previous opioid dependency.

Lactulose is useful for treatment of hemorrhoids because it produces a soft bowel movement without any straining.

Lactulose is helpful for treating children who withhold their bowel movements out of fear because when taken in sufficient quantity and then withheld, it produces a very insistent, irresistible and powerful urge to defecate.

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 Staphylococcal species in stool, with increase in non-urease producing Lactobacillus 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.

Lactulose has an overly sweet taste that can be completely masked by mixing it with fruit juice or desserts. It can take 24 to 48 hours to work, but generally produces results within 4 hours if taken on a daily basis. It is best taken at breakfast along with a bowl of bran cereal.

For stubborn cases of constipation, lactulose is sometimes combined with polyethylene glycol 3350Da, (sold as Miralax or Dulcolax Balance in the USA without prescription).

Some authorities recommend lactulose twice a day. However, an evening dosage can be problematic. When taken on a regular basis, it tends to work in about four hours. If given to small children who are in diapers, this is not a problem. However, for older children and adults, there is the ever present danger of voluminous defecation during sleep or being awake for hours on the toilet with a feeling of imminent expulsion. A juvenile or adult diaper is recommended along with protective plastic pants. This is especially true if a sleeping pill is taken.^{[citation needed]}

In common with other osmotic laxatives, lactulose can cause electrolytic imbalances in sensitive individuals (see side effects below). However, it tends to do this less because it does not rely on mineral salts to draw fluid into the intestinal tract and also because it relies on nonosmotic modes of action: It stimulates peristalsis through acidification and gas and increases feeling of urgency through enlarging the volume of the bowel contents.

Lactulose is sold over the counter (without prescription) in most countries in the world. In the United States and Austria, it requires a prescription over unfounded fears that it could be dangerous to diabetics. However, it is an indigestible sugar and has been proved to be safe even for them.

Hepatic encephalopathy

In treating hepatic encephalopathy, lactulose helps "draw out" ammonia (NH₃) from the body and is useful for preventing hyperammonemia caused as a side effect of administration of Depakote.

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). 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. However, lactulose can effectively be used as secondary prohylaxis of hepatic encephalopathy in patients with cirrhosis. Moreover, recent studies showed improved cognitive functions of cirrhotic patients with minimal hepatic encephalopathy treated with lactulose.

Lactulose, also an osmotic laxative, 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 three or four times a day with diarrhea and constant flatulence almost a certain side effect.

Lactulose Breath Test

Lactulose is used as a test of small intestine bacterial overgrowth syndrome (SIBO). Recently the reliability of it for diagnosing SIBO has been seriously questioned. 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.

Food Applications

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

Transit effect

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.

A regular daily consumption of galactofructose optimizes functioning of the intestinal tract by regulating intestinal transit. 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.

The daily dose recommended by the authorities is 10g per day. Very few side effects are observed. Transit effect of galactofructose does not affect gastric emptying nor protein and lipid metabolism.

Bifidogenic/prebiotic effect

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. 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. 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

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, 300mg calcium and 150mg magnesium the absorption of calcium and magnesium is enhanced.

Increased calcium absorption has also been observed in studies conducted with postmenopausal women, where a 9-day(s) programme of galactofructose consumption revealed higher levels of calcium in a dose–response way. These results reinforce those of various animal studies which show enhanced mineral absorption and improved bone strength.

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

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 has no taste but exhibits a sweetness which is equivalent to 0,6-0,8 (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 yoghurts, drink yoghurts, multi-juice drinks and bakery products including cereal bars, breakfast cereals and biscuits, 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.

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

Common side effects of lactulose are abdominal cramping, borborygmus, gas and pungent flatulence that some people find difficult to control in social situations. Excessively high dosage can cause explosive and uncontrollable diarrhea. In normal individuals, overdose is considered uncomfortable, but not life threatening. 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.

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.

External links

• Medline Plus