LACTULOSE IN THE THERAPY OF DIGESTIVE DISEASES

Lactulose is one of the most commonly used drugs in the treatment of hepatic encephalopathy and constipation. The main mechanisms of action of the drug are associated with its metabolism:

1) lactulose is a synthetic disaccharide that does not occur in nature;

2) there is no disaccharidase in the small intestine for its hydrolysis, and therefore it is not adsorbed;

3) lactulose hydrolysis is carried out by bacterial disaccharidases in the colon with the production of short-chain carboxylic acids of the aliphatic (fatty) series and various gases. The mechanisms of action of lactulose hydrolysis products are considered, as well as the feasibility of its use in constipation, hepatic encephalopathy, acute intestinal infections, cholelithiasis, hypercholesterolemia.

Carbohydrates that are taken with food are divided into mono-, di-, oligo- and polysaccharides. Their physiological significance is determined by the location and completeness of hydrolysis and absorption in the digestive tract. Most of them are digested and absorbed in the small intestine with the participation of pancreatic and intestinal amylase and disaccharidases. Only polysaccharides of plant cells (dietary fiber), resistant forms of starch and indigestible oligosaccharides (e.g. raffinose) enter the large intestine, where they are fermented by intestinal microflora [7].

The cecum is the main habitat of normal intestinal microflora, the number of which reaches up to 1014 colony-forming units, and the weight is up to 1.5 kg. The colonic microflora, according to the type of enzymes secreted, is divided into proteolytic (putrefactive) and amylolytic (fermentative). The main representatives of the proteolytic microflora are: Bacteroides, Proteus, Clostridium, Escherichia coli, Enterobacter, Ristella, most of which are recognized as potentially pathogenic. These microorganisms, with the participation of proteases and ureases, break down food protein into toxic amines, phenols, indoles, ammonia and other products that are absorbed and metabolized in the liver, turning into non-toxic compounds (for example, urea). The amylolytic (saccharolytic) intestinal microflora includes various species. Bifidobacterium, Bactobacillus, Streptococcusfaecalis. With the participation of bacterial amylases and disaccharidases, the hydrolysis of carbohydrates indigestible in the small intestine to organic acids and gases occurs.2 and CO2, and in some individuals and CH4 [9].

Short-chain carboxylic acids of the aliphatic (fatty) series perform a number of important biological functions. Utilized by the epithelium of the mucous membrane of the colon, they are a source of energy that ensures its functioning and regeneration. Entering the liver and general bloodstream with portal blood, they are used by hepatocytes and cells of other organs and tissues as nutrients. Short-chain carboxylic acids of the aliphatic series reduce the intraluminal pH level in the colon, which is accompanied by increased peristalsis, as well as inhibition of the growth of proteolytic microflora. Rapid adsorption of these acids in the distal colon improves the absorption of water, sodium, and other electrolytes [9].

Thus, microbial fermentation of indigestible carbohydrates ensures the conversion of non-absorbable food substrates into rapidly absorbed short-chain carboxylic acids of the aliphatic series, which reduces the osmotic pressure of the colonic contents, which increases the absorption of water and electrolytes, which reduces calories.

Lactulose is a chemical isomer of lactose, is a synthetic disaccharide consisting of galactose and fructose. This disaccharide does not occur in nature. In connection with which humans lack a disaccharidase capable of splitting it into the corresponding monosaccharides. Lactulose taken orally is practically not metabolized and is not absorbed in the small intestine and enters the colon unchanged. Under the influence of disaccharidase-saccharolytic microflora, lactulose, like other indigestible carbohydrates, is hydrolyzed to monosaccharides and ultimately to short-chain aliphatic carboxylic acids. This metabolic chain of lactulose conversion, with the formation of an excessive amount of short-chain aliphatic carboxylic acids, is responsible for its therapeutic effects in a number of digestive diseases and, primarily, in constipation and hepatic encephalopathy [7].

Constipation is not an independent disease. It is, as a rule, a symptom of many diseases of the digestive system and other systems. According to the Rome criteria (1999), diagnostic signs of functional constipation include the presence for at least 12 weeks, which do not necessarily have to be consecutive, over the past 12 months, of two or more of the following signs:

1) straining in >25% of defecations;

2) fragmented (bean-shaped) or hard stools in >25% of defecations;

3) feeling of incomplete evacuation in >25% of defecations;

4) feeling of anorectal obstruction, blockage in >25% of defecations;

5) manual assistance for relief in >25% of defecations (e.g., digital emptying, pelvic floor support);

6) fewer than 3 defecations per week [13].

Regardless of the etiology, the pathogenesis is reduced to the following mechanisms:

1) impaired propulsive activity of the colon due to hypomotor dyskinesia or atony, or spastic dyskinesia of the colon;

2) slowing of anorectal transit (anismus, conscious and unconscious disorder of sensitivity of the anorectal zone, Hirschsprung's disease);

3) presence of mechanical obstacles to the movement of chyme;

4) excessive absorption of water from the intestinal contents and, as a result, a decrease in the mass and compaction of the consistency of feces [4;6].

Constipation has a number of negative effects on both the digestive organs and the body as a whole. Coprostasis increases intraintestinal pressure, which is accompanied by the occurrence of a pain syndrome - "intestinal colic". Intestinal colic often simulates appendicitis, acute and chronic cholecystitis, pancreatitis, intestinal obstruction, with the consequences that follow from this. High pressure in the colon disrupts evacuation from the small intestine, including the duodenum, and from the stomach, which contributes to the development of duodenogastric and gastroesophageal reflux. Stasis of intestinal contents leads to a disruption of the normal composition of the intestinal microflora and, first of all, to excessive bacterial growth in various parts of the intestine, often with the development of an inflammatory process. A change in the composition of the microflora, especially an increase in proteolytic strains, is accompanied by the appearance of xenobiotics in the intestine - products of protein decay. The latter, absorbed, increase the functional load on the liver with the development of fatty degeneration of hepatocytes, reactive hepatitis. With constipation of any origin, the rectum and anus are involved in the pathological process, which is manifested by the presence of recurrent hemorrhoids, anal fissures, sphincteritis, coccydynia, etc. In patients with constipation, purulent-inflammatory changes in the skin, allergic reactions, etc. are often noted.

The main directions in the treatment of constipation, regardless of its etiology and pathogenesis, are:

a) normalization of the propulsive activity of the colon;

b) increase in the volume and softening of the consistency of the intestinal contents. For this purpose, a wide range of therapeutic effects is used. It is usually recommended to increase physical activity, increase the consumption of dietary fiber and fluid. If normalization of bowel movements is not achieved, laxatives are used. The latter, depending on the mechanism of action, are divided into the following subgroups [1; b]:

• Softening feces (liquid paraffin);
• Increase the volume of intestinal contents (bran, seeds);
• Increase the osmotic pressure of intestinal contents (do not absorb salts, polyhydric alcohols);
• Irritants (anthraquinones, etc.)
• Prokinetics (cisapride, etc.)

Most of the above laxatives adversely affect the processes of digestion and absorption, electrolyte metabolism, and the composition of the intestinal microflora. A number of them (anthronoids and diphenylmethane derivatives) have oncogenic potential and their use is prohibited in some countries. Tolerance develops to most laxatives and a significant increase in dose is required to achieve the effect. Many of the drugs are not recommended for children, the elderly, pregnant and lactating women, as well as in the presence of a number of diseases of the internal organs and the nervous system.

The next important aspect is the therapy of portosystemic encephalopathy (PSE). a potentially reversible disorder of the functions of the central nervous system associated with hepatocellular insufficiency. PSE is a complex neuropsychiatric syndrome characterized by a disorder of behavior, consciousness, neuromuscular disorders that occurs in patients with decompensated liver diseases and, primarily, with cirrhosis. The main pathogenetic mechanism of PSE is associated with the effect of neurotoxins coming from the intestine, the synthesis of false mediators from aromatic amino acids and the enhancement of GABA-ergic transmission of nerve impulses in the brain [5; 12].

In healthy people, potentially toxic substances that are formed in the colon during protein hydrolysis with the participation of proteolytic microflora are neutralized by hepatocytes. When portocaval anastomoses function and/or a decrease in the number of hepatocytes (for example, in cirrhosis of the liver), these toxic products enter the general bloodstream, penetrate the blood-brain barrier and lead to the development of PSE [2; 3; 14]. There are 5 degrees of severity of hepatic encephalopathy: from latent, in which there are no clinical symptoms, and its signs are detected only by psychometric tests to coma. At the same time, even with compensated cirrhosis of the liver (Child-Pugh class A), 70% of patients have signs of latent PSE [1].

The main provoking factors for the development of PSE are [8]: 1) an increase in the intestine of substrates for putrefaction (blood, food protein); 2) an increase in hepatocellular insufficiency due to hepatocyte necrosis caused by the activation of liver cirrhosis (alcohol, drugs, viral infection, etc.); 3) an increase in blood flow through portocaval anastomoses (portal crises, ascites buildup, portocaval anastomoses).

Lactulose is the most widely used and highly effective drug in the complex treatment of PSE [2; 3]. The action of lactulose in PSE can be realized through a number of mechanisms: 1) inhibition of the production of ammonia and other xenobiotics; 2) utilization of the ammonia formed; 3) impaired absorption and rapid excretion of ammonia with feces [1b].

Numerous studies have confirmed the effectiveness of lactulose in PSE and it currently ranks first among the drugs in the treatment of this syndrome. From the conducted clinical trials, it was shown that lactulose in the treatment of PSE is significantly superior to placebo; in terms of effectiveness, it can be compared with the combination of neomycin with a laxative. At the same time, the therapeutic effect of lactulose is achieved faster than that of neomycin.

Lactulose has found wide application for the decontamination of chronic carriers of salmonella. Salmonella are common pathogenic bacteria that cause the development of enteritis. Salmonella form colonies, mainly in the terminal ileum and in the colon, where an inflammatory process develops with massive exudation of water, electrolytes, proteins, followed by diarrhea, fever, nausea, vomiting and abdominal pain. The duration of symptoms is from 2 to 4 days, while salmonella is excreted for another 4-6 weeks. Chronic carriage is much less common. If the disease proceeds without complications, antibacterial chemotherapy is not performed, as this may increase the period of bacterial excretion. Correction of water and electrolyte balance is performed. Only children under one year of age and patients with severe concomitant diseases can be prescribed cotrimoxazole, ampicillin or quinolones. Treatment of chronic carriers is of great social importance, as it prevents infection of others. Doses of lactulose (dufalac) are selected individually, on average 15-30 ml per day, the duration of treatment is 2-3 weeks. Clinical trials have shown that taking lactulose significantly shortened the period of pathogen excretion.

A similar effect was obtained with other gastrointestinal infections, in particular, those caused by Yersinia, Shigella, and rotavirus infections.

Lactulose exhibits a number of positive metabolic effects on the body, and therefore it can be used in such completely different diseases as urinary tract infection, gallstone disease, hypercholesterolemia, chronic renal failure, as well as as a prebiotic to restore the normal composition of the intestinal microflora. after antibiotic therapy, radiation and chemotherapy.

The therapeutic effect of lactulose in the above conditions is based on an increase in the growth of saccharolytic and, in particular, bifidum bacteria, inhibition of the proliferation of proteolytic microflora and restriction of the translocation of intestinal bacteria into the biliary and urinary systems. Taking lactulose leads to excessive excretion of bile acids with feces and, as a result, to their increased formation in the liver from cholesterol. The latter leads to a decrease in cholesterol content in the blood and bile, which is desirable in cholelithiasis and hypercholesterolemia.

Thus [10; 1b], lactulose is a highly effective and safe drug in the treatment of encephalopathy, as well as a prebiotic that promotes the growth of normal intestinal microflora.

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