The active ingredient of Duphalac® is lactulose. This sugar does not occur naturally but is a disaccharide synthesized from lactose. The close similarity of these names easily causes confusion. The physiological differences, however, are considerable and clinically relevant.
The principal action of Duphalac® derives from the fact that the molecule cannot be cleaved by enzymes of the small intestine and is therefore still intact on reaching the large intestine, where it is degraded by specific bacteria and broken down into low molecular weight organic acids, mainly lactic, acetic, butyric and propionic acid. The intestinal contents are thereby acidified and the osmotic pressure in the colon increased.
This pharmacologically simple action of Duphalac® has greatly varying effects depending on the dosage. This explains the many different uses of Duphalac®: the prevention and treatment of portosystemic encephalopathy (PSE) and constipation, and the promotion of defecation and fecal excretion of salmonellae in enteritis.
Numerous studies confirm the effectiveness and lack of side effects of Duphalac®. This permits the often necessary long-term treatment of chronic obstipation with Duphalac® without undesired effects such as electrolyte losses or signs of dependency. So, despite being a synthetic substance, Duphalac® has been proven to act extremely physiologically. Duphalac® could also therefore be described as chemically defined roughage.
The active ingredient of Duphalac® is lactulose, a synthetic disaccharide not occurring in nature, in which each molecule of galactose is linked to a molecule of fructose by a beta-1,4 bond. These linked monosaccharides are the reason why lactulose cannot be degraded either by animal or human enzymes.
Duphalac® is synthesized by chemical rearrangement (isomerization) from lactose.
The structural formula of lactose and lactulose is shown in Figure 2 below.
Duphalac® powder is a white or off-white, sweet-tasting, odourless crystalline powder. Duphalac® powder is freely soluble in water, sparingly soluble in methanol and practically insoluble in ether. Duphalac® syrup is clear and slightly yellowish.
Duphalac® contains small amounts of other sugars originating from the synthetic process:
Syrup: 100 ml contain:
< 11 g galactose, < 7.5 g lactose, < 2.5 g tagatose, < 2 g epilactose and < 1 g fructose, equivalent to about 1.4 BU (max. about 65 kcal)
Powder: 10 g contain:
< 0.25 g galactose, < 0.2 g lactose, < 0.3 g tagatose, < 0.15 g epilactose and < 0.1 g fructose, equivalent to about 0.04 BU (max. 2 kcal)
The specifications reflect manufacturing requirements. The actual values are sometimes much lower.
The disaccharide Duphalac® does not occur naturally and the human body has no enzymes capable of hydrolyzing Duphalac® to the respective monosaccharides (galactose and fructose). Duphalac® therefore passes through the gastrointestinal tract and reaches the colon unchanged and without appreciable absorption. Only about 0.25 - 2.0 % of an oral dose is absorbed unchanged in the small intestine, possibly by passive diffusion.
Distribution
Duphalac® is not distributed to body tissues since the active ingredient is normally not absorbed. Any small amounts absorbed are eliminated unchanged and mainly by renal excretion.
Metabolism - the intestinal flora
The intestine of adult humans contains about 1014 bacteria comprising of 400 different species and subspecies with a total weight of 1 to 1.5 kg. Usually in healthy equilibrium, proteolytic and saccharolytic bacteria cooperate in degrading the residual protein and nondigestible carbohydrates reaching the large intestine.
Some typical representatives of the intestinal flora of adult humans
primary metabolism type
proteolytic (* potentially pathogenic)
saccharolytic (# health promoting organisms)
Bacteroides
Bifidobacterium (various species) #
Proteus
Lactobacillus (various species) #
Clostridium *
Streptococcus faecalis
Ristella
Escherichia coli *
In the colon, Duphalac® is an ideal nutrient for the saccharolytic bacteria which grow and rapidly multiply during Duphalac® administration. In this situation the competition for nutrients results in suppression of the proteolytic, toxin producing, potentially pathogenic intestinal flora.
Duphalac® is first hydrolyzed to the monosaccharides (fructose and galactose) and then to low molecular weight organic acids, known as short chain fatty acids (SCFA). This causes a decrease in the concentration of medium chain fatty acids (with 4 to 6 C atoms) which are ascribed toxic effects, and originate from protein degradation.
Bacterial transformation of Duphalac® to short chain fatty acids induces a number of physiological changes in the colon. These are ultimately responsible for the preventive and therapeutic effects of Duphalac® in constipation, portosystemic encephalopathy, salmonella enteritis and other potential indications.
At daily doses of 45 - 50 g Duphalac® is metabolized completely, while at higher dosage levels part of the dose is eliminated unchanged; during continuous admin-istration of Duphalac®, however, a metabolizable dose of 95 g is rapidly achievable. Moreover, unchanged Duphalac® also appears to decrease the concentratiion of ammonia in the small intestine.
The biotransformation products of Duphalac®, the short chain fatty acids, acidify the proximal and - dose-dependently - the distal colonic contents. This limits the value of fecal pH measurements as an indicator of lactulose efficacy since relatively low acidic or neutral fecal pH values do not necessarily imply lacking efficacy.
Elimination
Very small amounts of unchanged Duphalac® appear in the urine. Usually only traces are found in bile and faeces.
Toxicological properties
Acute toxicity: Animal studies into acute toxicity did not result in any particular sensitivity.
Chronic toxicity: Studies on various animal species into chronic toxicity produced no indications of toxic effects.
Tumour-causing and mutagenous potential: A long-term animal study produced no indications of carcinogenic potential. There are no studies into mutagenous potential available.
Reproduction toxicity: Studies on three animal species produced no indications of teratogenic effects. Lactulose is not known to have any harmful effects when taken during pregnancy or while nursing.
Cariogenic potential: Saccharolytic bacteria are also present in the oral cavity and on the teeth. Especially during chronic administration, therefore, the cariogenic potential of the sugar is of interest. Lactulose showed a low in vivo acidogenic potential, is thus of only minor cariogenic relevance and much less harmful to teeth than sucrose.
Duphalac® has two main components of action in constipated patients:
Duphalac® is not cleaved and absorb-ed in the small intestine and thus reaches the large intestine, where it is broken down into short chain fatty acids (lactic, acetic, propionic and butyric acid) by bacterial degradation. This lowers colonic pH with stimulation of peristalsis.
Degradation to short chain fatty acids (SCFA) also increases the osmotic pressure in the intestinal lumen. A dose-dependent acceleration of colonic transit results from an increase in fecal volume due to intraluminal water retention and enhanced intestinal peristalsis.
The third effect probably does not contribute to the primary, acute action (2 to 10 hours). Since Duphalac® is a source of carbohydrates and energy for saccha-rolytic bacteria, their biomass in the intestine can increase. A study in healthy volunteers showed that bifidobacteria, for example, increased by three magnitudes (from about 10 to about 10). This could result in an increased bowel filling volume.
Duphalac® has a less pronounced osmotic effect (about fourfold increase) than non-absorbable salts (more than tenfold increase). This value is too low for withdrawal of body water, and somewhat less water is absorbed from the large intestine. This represents only a fraction of the water reabsorbable in the large intestine (9 to 10 liters/day).
The combination of two physiologically moderate effects results in a clinical action comparable to that of other laxatives. Since intestinal bacteria metabolize Duphalac® very rapidly, the onset of action is already observed a few minutes after the active ingredient enters the colon. On an empty stomach, this can occur after only one to two hours.
If the saccharolytic flora is insufficient, it first has to grow in order to produce, after one to two days, sufficient amounts of metabolites from a single dose of Duphalac®.
Duphalac® is a preferred carbohydrate source for lactate producing bacteria (especially various species of Bifidobacterium and Lactobacillus), which can therefore increase considerably in mass. The associated increase in volume can induce a delayed, secondary laxative effect.
Mechanism of action in portosystemic encephalopathy
The precise mechanism of action of Duphalac® in hepatic encephalopathy must be regarded as still partly unclear. Several theories regarding the mechanism of action have been advanced or are currently under discussion:
Lactulose acidifies the contents of the colon and thus inhibits bacterial ammonia synthesis.
Lactulose changes the bacterial metabolism, resulting in increased carbohydrate metabolism and slower protein breakdown.
Lactulose acts as a source of carbohydrates for saccharolytic bacteria and inhibits the breakdown of amino acids to NH3.
Lactulose is an important energy supplier for saccharolytic bacteria. The growing volume of bacteria uses ammonia and amino acid nitrogen to breakdown bacteria protein.
Because lactulose inhibits bacterial urea breakdown, less ammonia accumulates as a degradation product.
Lactulose speeds up colon passage. This means there is less time for ammonia to form and that it is eliminated more quickly.
Lactulose reduces the proportion of ammonia in the Ileum, and glutamate ammonia is reduced – possibly through inhibition of the glutaminases, or through hydrogen bonding to intact lactulose molecules or through another unknown physio-chemical effect.
Lactulose is taken orally. The dosages specified here are meant as a guideline only and must always be adjusted to meet the individual requirements of the patient depending on severity and development of the symptoms.
Constipation
Starting dose
Maintenance dose
Adults
10-45 ml
10-25 ml
Children
(7-14 years)
15 ml
10-15 ml
Children 1-6
(1-6 years)
5-10 ml
5-10 ml
Babies
5 ml
5 ml
Portosystemic encephalopathy (PSE)
Dosage should be administered in gradually increasing amounts.
Adults:
Starting with 7.5 to 15 ml Duphalac® Syrup corresponding to 5 to 10 grams of lactulose three to four times daily, increasing to 30 to 45 ml Duphalac® Syrup corresponding to 20 to 30 grams of lactulose three to four times daily.
Dosage is to be adjusted so that two to three soft stools are passed daily.
Duphalac® can be taken dissolved or diluted in water or other liquids. It can be taken independently of meals.
The laxative effect can take place after two to ten hours. If dosage is insufficient, it can take 24 to 48 hours before the first bowel movement takes place.
The duration of treatment depends on how symptoms develop. Numerous studies confirm the effectiveness and tolerability of Duphalac®. This permits the often necessary long-term treatment of chronic obstipation with Duphalac® without undesired effects such as electrolyte losses or signs of dependency.
Duphalac® works gently and safely, and does not put strain on either the coronary circulatory system or the kidneys. There is no risk of addiction or misuse. In addition, Duphalac® is neither mutagenous nor genotoxic. These properties mean that Duphalac® is suitable for the treatment of a broad spectrum of patients, as confirmed by numerous studies.
Some of the patient populations studied are to be particularly emphasized since in these cases some laxatives were either contraindicated or their effect could not be sufficiently controlled, at least over prolonged periods. Suitable treatment with Duphalac®:
Constipation in young children, children and adolescents
Constipation in pregnancy and lactation
Constipation in physically handicapped patients
Constipation in the elderly
Duphalac® in laxative abuse
Duphalac® after hemorrhoidectomy
Opiate-induced constipation
Vincristine-induced constipation
The following patients can also be successfully treated with Duphalac®:
The bowel of adult humans contains about 10 bacteria comprising more than 400 different species and subspecies representing a total weight of 1 - 1.5 kg equivalent to the weight of the liver. Bacteria are single cell organisms and, unlike tissue, are not organized according to function. In other words, they are capable of performing all vital metabolic processes. Similar to the liver, the intestinal flora in its totality thus represents an enormously large and complex metabolic organ in the human body. An organ of such importance naturally has far reaching effects on human health.
One of the predominant bacteria in the large intestine is the genus Bifidobacte-rium. It has pronounced immunological properties of various kinds. Lactulose as an ideal nutrient for bifidobacteria and other lactate producers specifically pro-motes the growth of these genera, since potentially pathogenic organisms like E. coli, Clostridium or salmonellae can hardly metabolize lactulose and are suppressed by bifidobacteria. Bacteria generally cannot colonize the large intestine permanently. The suitable approach to counteracting abnormalities of bowel colonization - for prophylaxis and therapy - therefore consists in enhancing the existing intestinal flora, which is adapted to the human body, in a physiological manner. Lactulose administration can bring about marked changes in the intestinal flora persisting for considerable periods after treat-ment termination. The associated changes in the production of short chain fatty acids, potentially toxic aromatics and in the activity of bacterial enzymes (azoreductase, 7-a-dehydroxylase, ß-glucuronidase, nitroreductase, urease etc.) and their products have a considerable impact on the environment and the potential toxicity of the intestinal contents.
Overall, Duphalac® is a suitable means of exerting a lasting positive influence on the health-promoting intestinal flora.
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