Nifuroxazide

Pharmacological properties

nifuroxazide is an antimicrobial derivative of nitrofuran. the antimicrobial and antiparasitic properties of nifuroxazide are due to the presence of an amino group. local activity and the absence of penetration into the organs and tissues of the body determines the uniqueness of nifuroxazide in comparison with other nitrofuran derivatives, since, in addition to the antidiarrheal effect, there are no systemic effects. effective against gram-positive and gram-negative bacteria: streptococcus pyogenes, staphylococcus aureus, e.coly, salmonellae, shigellae.

Pharmacokinetics After oral administration, nifuroxazide is practically not absorbed in the digestive tract and does not enter the organs and tissues; more than 99% of the drug taken remains in the intestine. Biotransformation of nifuroxazide occurs in the intestine. Nifuroxazide and its metabolites are excreted in the feces. The excretion rate of the drug depends on the amount of medication taken and gastrointestinal motility.

In therapeutic doses, nifuroxazide practically does not suppress the normal intestinal microflora, does not cause the appearance of stable microbial forms, as well as the development of cross-resistance of bacteria to other antibacterial drugs. The therapeutic effect is achieved from the first hours of treatment.

Indications

Acute diarrhea of ​​infectious etiology.

Application

Capsules are taken orally, regardless of food intake.

Adults: 200 mg (2 capsules of 100 mg or 1 capsule of 200 mg) 4 times a day. The daily dose of nifuroxazide is 800 mg.

Children over the age of 6 years: 200 mg each (2 capsules 100 mg each 1 capsule 200 mg) 3-4 times a day. The daily dose of nifuroxazide is 600-800 mg.

The duration of treatment is no more than 7 days.

The suspension is taken orally, regardless of food intake. Before use, the suspension should be shaken.

Children from the age of 2 years: 5 ml of suspension 3 times a day.

Adults: 5 ml of suspension 4 times a day.

The duration of treatment is no more than 7 days.

Contraindications

Hypersensitivity to nifuroxazide, other 5-nitrofuran derivatives or other components of the drug. suspension - children under the age of 2 years. capsules - children under the age of 6 years.

Side effects

Enterofuril, like any medicine, can cause adverse reactions. may cause temporary abdominal pain, nausea, increased diarrhea. these symptoms do not require discontinuation of treatment. allergic reactions are possible, including rash, urticaria, angioedema, anaphylactic shock. the occurrence of an allergic reaction requires discontinuation of the drug.

special instructions

Treatment with nifuroxazide does not exclude dietary regimen and rehydration. if necessary, concomitant rehydration therapy is used depending on the age and condition of the patient and the severity of diarrhea. if diarrhea does not stop after 3 days of using the drug, you should review the dosage regimen and decide on rehydration.

Rehydration should be a key element in the treatment of acute diarrhea in children. Children should be given frequent (every ¼ h) fluid intake.

Prevention or treatment of dehydration should be carried out by oral or iv solutions. If rehydration is prescribed, it is recommended to use the solutions intended for this purpose, in accordance with the instructions for dilution and use. The prescribed volume of oral rehydration solutions depends on weight loss. In case of severe diarrhea, intense vomiting and refusal to eat, iv rehydration is required.

If there is no need for such rehydration, compensation should be made for fluid loss by consuming a large number of drinks containing salt and sugar (based on the average daily requirement of 2 liters of water).

It is necessary to take into account dietary recommendations for diarrhea: avoid eating fresh vegetables and fruits, spicy foods, frozen foods and drinks. Rice should be preferred. The decision on the use of dairy products is made depending on the specific case.

If diarrhea is accompanied by clinical manifestations that indicate the progression of the disease (general condition worsening, fever, intoxication symptoms), Enterofuril should be prescribed in combination with antibacterial drugs used to treat intestinal infections, since the drug is not absorbed in the intestine and does not enter the systemic circulation. The drug is not prescribed as monotherapy for the treatment of intestinal infections complicated by septicemia.

Enterofuril contains sucrose, which should be considered when prescribing the drug to patients with diabetes mellitus. It is not recommended to prescribe the drug to patients with hereditary disorders of tolerance to sucrose, fructose.

The suspension preparation contains methyl parahydroxybenzoate (E218), which can cause an allergic reaction.

During treatment, drinking alcohol is strictly prohibited due to the risk of developing a disulfiram-like reaction, which is manifested by exacerbation of diarrhea, vomiting, abdominal pain, sensation of heat on the face and upper body, hyperemia, tinnitus, shortness of breath, tachycardia.

Use during pregnancy or lactation. There is insufficient data on the possible teratogenic and fetotoxic effects when using nifuroxazide during pregnancy. Therefore, as a precaution, the use of nifuroxazide during pregnancy is not recommended.

The drug can be used during lactation, subject to short-term treatment.

Children. Enterofuril in capsule form is used in children over the age of 6 years. Enterofuril in the form of a suspension is not prescribed for children under the age of 2 years.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Does not affect.

Interactions

Nifuroxazide is not recommended to be used simultaneously with sorbents or drugs containing alcohol, drugs that can cause antabuse reactions, and with drugs that inhibit central nervous system.

Overdose

Not described. if the therapeutic dose is exceeded, it is necessary to rinse the stomach and prescribe symptomatic treatment.

Storage conditions

Capsules - does not require special storage conditions. suspension - at a temperature not exceeding 30 ° C. do not freeze.

Actual information

Gastrointestinal infections are a serious problem worldwide. In the structure of acute diarrhea (lasting less than 1 week), gastrointestinal infections are noted in 65–80% of cases (begovic b., 2016). Today, treatment of diarrhea is predominantly associated with symptomatic therapy, which includes rehydration in accordance with the degree of dehydration, including complex saline solutions, diet and the use of probiotics. however, the inclusion in the scheme of antibacterial drugs with an appropriate spectrum of action can significantly reduce the duration of the disease (from 5-7 to 1-2 days).

The best choice in the treatment of acute diarrhea of ​​infectious etiology is antibacterial drugs with minimal absorption, since they act only in the intestinal lumen and do not have a systemic effect. This ensures their greater efficiency and safety at the same time. In addition, such a local action eliminates the detrimental effect of antibacterial drugs on the microflora outside the gastrointestinal tract.

One such drug is Enterofuril, which according to the ATC classification belongs to the group of antimicrobial drugs used to treat intestinal infections.

The mechanism of action of Enterofuril and its clinical use

Therapeutic effects Enterofurila are provided with its active substance - nifuroxazide. The antimicrobial and antiparasitic properties of this drug, as well as other nitrofurans, are associated with the nitrogen group (NO₂) in the structure of its molecule. The drug inhibits the respiratory chain and the cycle of tricarboxylic acids of microorganisms, blocking the activity of dehydrogenases. In addition, it is able to destroy the cell membrane of the pathogen and reduce the production of exotoxins.Effective against microorganisms such as Streptococcus pyogenes, Staphylococcus pyogenes, E. coli, Salmonellae spp., Shigellae spp., Enterobacter spp., Klebsiella spp., Proteus spp. (Begovic B., 2016). Nifuroxazide is practically not absorbed in the digestive tract - more than 99% of the drug remains in the intestinal lumen. In the intestinal wall, its biotransformation occurs. As a result, about 20% of unchanged substance is excreted with feces, the rest is its metabolites. In standard therapeutic doses, nifuroxazide has a bacteriostatic effect, and if the dose is increased, it is bactericidal (Vanhoof R., 1981). Such a wide spectrum of action and the absence of a systemic effect make empirical assignment possible. Enterofurila before specifying the causative agent of diarrhea. It is noteworthy that nifuroxazide also has a certain positive effect on diarrhea of ​​viral origin, as it prevents the attachment of bacterial superinfection, activates the immune response and promotes the regeneration of the gastrointestinal mucosa. It is also very important that nifuroxazide, even with prolonged use, does not upset the balance of normal intestinal microflora (Buisson Y., 1989).

First of all, nifuroxazide is used to treat bacterial dysentery and foodborne toxicoinfection (Bulbulović-Telalbasić S., 1991) in adults (Bourée P., 1989) and children (Lapeyre-Mestre M., 2004). One of the main reasons for its appointment is travelers diarrhea - a kind of intestinal infection that occurs in Europeans after traveling to Africa or Asia (Meuris B., 1995). Nifuroxazide can also be used to prevent this disease if a person has to travel to a region where outbreaks of cholera or other intestinal infections are observed (Scarpignato C., 1995).

In addition, the moderate activity of nifuroxazide against Giardia lamblia allows treating not only bacterial, but also parasitic lesions of the intestine (Cedillo-Rivera R., 1992).

It is recommended to use nifuroxazide for the treatment of diarrhea associated with inhibition of normal intestinal microflora against the background of previous systemic antibiotic therapy.

Enterofuril It is also prescribed as a component of eradication therapy in chronic inflammatory diseases of the upper gastrointestinal tract (Scherbakov P.L. et al., 2011).

There is experience of effective treatment of chronic diarrhea caused by Isospora belli in patients with AIDS (Meyohas M.C., 1990).

Promising is the use of nifuroxazide and its derivatives in the treatment of diseases caused by MRSA (Fernandes M.B., 2012), as well as in the treatment of Chagas disease, a specific South American infectious disease caused by Trypanosoma cruzi (Palace-Berl F., 2015). The expectation of a therapeutic effect is based on the property of the drug to inhibit lipoamide dehydrogenase, trypanothion reductase and glutathione reductase, which are key enzymes of the biochemical processes of this intracellular parasite (Blumenstiel K., 1999).

In addition, there is a role for nifuroxazide in the prevention of colorectal cancer in the treatment of multiple intestinal infections (Duffour J., 2002).

Although nifuroxazide has been used to treat infectious diarrhea since 1966, it has other uses (Bailly C., 2019). For example, a promising direction is its use in oncology as a means for targeted therapy (Misra S.K., 2017). Studies have proven the anticancer activity of nifuroxazide. This applies primarily to colon cancer. In 2008, it was found that the drug effectively inhibits metastasis of the tumor into the lungs and abdomen due to its effect on the transmission of the Stat3 signal (responsible for cell apoptosis, cell proliferation and angiogenesis) - it inhibits the migration of cancer cells and their invasion, inhibiting Stat phosphorylation 3 tyrosine residues, as well as destroying caspase-3 and inhibiting the expression of Bcl-1. As a result, the viability of tumor cell clones decreases - the proliferation index decreases, apoptosis of tumor cells is induced, and the process of metastasis is disrupted. In addition, the immune antitumor response is stimulated - the tumor mass infiltration of CD8 + T-lymphocytes increases. These effects of nifuroxazide are dose dependent (Ting-Hong Y., 2017).

Similarly, nifuroxazide affects breast cancer cells.In addition to the mechanisms of action described for colorectal cancer, in this case there is also inhibition of the expression of matrix metalloproteinases MMP-2 and MMP-9, which ensure the process of invasion of cancer cells (Yang F., 2015).

Nifuroxazide can also be used to treat melanoma. In addition to the already mentioned mechanisms of influence on the tumor, its ability to interrupt the mitosis process in the G2 / M phase is noted, the result of which will be the death of the tumor cell. Selective binding to different fractions of aldehyde dehydrogenase (Peterson R.T., 2018) dramatically reduces the potential for maintaining clones of tumor-initiating stem cells (Sarvi S., 2018). The immune antitumor response is also stimulated by increasing the number of myeloid suppressor cells (Youngxia Z., 2016). Similar effects are also observed for papillary thyroid carcinoma cells (Hu Y., 2019).

The experience of its use in the treatment of hepatocellular carcinoma (Zhao T., 2017), osteosarcoma (Luo Y., 2019), multiple myeloma (Nelson E.A., 2008) is also described.

However, it must be borne in mind that the majority of the antitumor effects of nifuroxazide require a parenteral route of administration for systemic action. In animal experiments, the drug is administered intraperitoneally, that is, directly into the abdominal cavity. In this case, the property of the peritoneum is actively absorbed the active substance.

In addition, the mechanism of inhibition of Stat3 by nifuroxazide can be used in transplantology - it has been proved in experiments (Jia H., 2017) that in case of allogeneic bone marrow transplantation, the drug inhibits transplant versus host immunological reactions (mediated by T-lymphocytes of types CD4 + and CD25 +) and thereby reducing the risk of severe post-transplant complications. The same mechanism provides the nephroprotective properties of the drug in diabetic nephropathy (Said E., 2018) by eliminating oxidative stress and reducing the activity of apoptotic enzymes (caspase-3/8/9) (Elsherbiny N.M., 2018).

Dosing Enterofuril

For ease of use Enterofuril available in various forms - both in capsules of 100 and 200 mg of active ingredient, and in suspension. The standard frequency of admission is 4 times a day (for children over the age of 6 years - 3-4 times a day), and the total duration of the course of treatment should not exceed 7 days. Moreover, for adults and children over the age of 6, a single dose is 200 mg. Enterofuril in capsule form is used in children over the age of 6 years. For children aged 2-6 years, a suspension of 5 ml is indicated 3 times a day. Not prescribed for children under 2 years of age. If an adult patient for some reason can not use the drug in capsules, then he is prescribed a suspension, taking into account the fact that 5 ml of it contains 200 mg of the active substance.

The optimal effect of therapy Enterofuril it will be observed if it is correctly combined with a sufficient amount of liquid (oral or parenteral rehydration), as well as with diet and the use of probiotics, which will allow faster restoration of intestinal microflora. The diet should include only sparing foods with a moderate amount of fiber, since a large amount of it can mechanically irritate an already damaged intestinal mucosa. It is also necessary to understand that the simultaneous use of sorbents significantly reduces the effectiveness of antibiotic therapy.

Features of use and possible side effects

Nifuroxazide is practically not absorbed in the gastrointestinal tract, therefore, contraindications to its use were previously limited only to individual intolerance to nitrofurans. Of the adverse reactions, the following are possible: the occurrence of temporary abdominal pain, nausea, increased diarrhea (symptoms do not require discontinuation of the drug); allergic reactions are possible, including rash, urticaria, Quinckes edema, anaphylactic shock (requires discontinuation of the drug). However, the following cases are described in the literature.

First of all, with systemic use, nitrofuroxazide is characterized by a mutagenic effect (Quillardet P., 2006), most likely associated with the ability to influence the reproduction and differentiation of stem cells. Therefore, it is strictly contraindicated for pregnant women to use the drug.

A case of acute pancreatitis, which developed as a result of taking nifuroxazide, is described. Presumably, the pathological process developed according to the immunoallergic type (Shindano A., 2007). Side effects of systemic use of the drug include granulocytopenia with a leukemoid reaction (Karaaslan Y., 1999), diffuse rhabdomyolysis (Bismuth C., 1972) and common skin reactions such as pustular exanthema (Machet L., 1997) or nodular prurigo (Kieć- Swierczyńska M., 1998).

Nifuroxazide is strictly forbidden to be used in combination with alcohol - there is a high risk of developing disulfiram-like reactions (teturam-like reactions, antabuse effect), which are manifested by severe nausea, vomiting, chills and chest pain.

findings

In this way, Enterofuril It is an effective and convenient drug for the treatment of acute diarrhea of ​​infectious etiology. Along with this, in relation to its active substance, the same global trend is observed as that of most other classic drugs - a detailed study of the mechanisms of action, the effect on physiological and pathological processes in the human body, as well as the search for new fields of application based on the data obtained. The ability of nifuroxazide during systemic use to influence the processes of reproduction, growth and differentiation of epithelial cells, the immune response against tumors, transplants and the body’s own tissues has already been established. These effects can be used in clinical practice not only for treatment (this is still only in the future), but also for the prevention of colon cancer.