RU2444372C1 - Method for treating acute hepretic stomatitis in children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to infectious diseases, and can be used for treating acute herpetic stomatitis in children. That is ensured by oral administration of Reaferon EC-Lipint 250000 IU twice a day for 3 days with local application of a thin layer of Infagel ointment on affected oral mucosa twice a day for 5 days.

EFFECT: method enables reducing length of treatment and providing better therapeutic effect ensured by combined local and general antiviral and immunomodulating activities with no side effects.

4 tbl, 2 ex

Description

The invention relates to medicine, namely to infectious diseases, and can be used to treat acute herpetic stomatitis in children.

The problem of diseases of the oral mucosa is one of the most important in dentistry. A special place here is occupied by acute herpetic stomatitis (OGS), since it accounts for more than 80% of all diseases of the oral mucosa in children [Drobotko LN, Strakhova S.Yu. Clinic, diagnosis and treatment of acute herpetic stomatitis in children. - M., - 2006].

OGS not only takes the first place among all lesions of the oral mucosa, but also enters the leading group among all infectious diseases of childhood. In 71% of cases, OHS is common in children aged 1 year to 3 years. This is due to the fact that at this age in children the antibodies received from the mother interplacental disappear, as well as the lack of mature systems of specific immunity. Among older children, the incidence is significantly lower due to acquired immunity after a herpetic infection in its various clinical manifestations [Elizarova V.M., Drobotko L.N., Strakhova S.Yu. New drugs in the treatment of acute herpetic stomatitis in children. - M., - 2006]. At the same time, in every 7-10th child, OGS early becomes chronic with periodic relapses - chronic recurrent herpetic stomatitis (HRGS).

For the first time, the role of the herpes simplex virus (HSV-1) in diseases of the oral mucosa was indicated at the beginning of the 20th century by N.F. Filatov (1902). He suggested a possible herpetic nature of the most common acute aphthous stomatitis among children. Evidence was obtained later when HSV-1 antigens were detected in the epithelial cells of the affected areas of the oral mucosa. Currently, the combined use of methods of virologic, serological and immunofluorescence studies confirms that acute herpetic stomatitis is one of the clinical forms of primary herpetic infection [3].

Acute herpetic stomatitis can occur in mild, moderate and severe forms. The development of the disease goes through 5 periods: incubation, prodromal, the period of the development of the disease, extinction, and clinical recovery. The severity of the disease and the periods of its development reflect the severity of violations of the body's protective barriers. Moderate and severe forms of stomatitis lead to a sharp inhibition of natural immunity, which is restored 7-14 days after the clinical recovery of the child [Pokrovsky V.I., Pak S.G., Briko I.I. Infectious diseases and epidemiology. - M., Geotar-Med, - 2003].

Analyzing the factors that provoke the development of herpetic stomatitis, it should be noted that many of them are accompanied by a decrease in the body's production of interferon - the most important factor in the body's non-specific antiviral resistance.

Interferons have three main properties: antiviral, immunomodulatory and antiproliferative and affect many reactions of the infectious process. The biological effect of IFN is characterized by universality (active against many DNA and RNA-containing viruses), specific tissue activity (active only in homologous structures) and aftereffect (viruses are suppressed in the treated cells even after IFN removal). Interferons do not have a direct antiviral effect, their antiviral effect is manifested during the period of reproduction of the virus by the active inclusion in the metabolic processes of cells treated with IFN. The protective effect of a viral infection is realized mainly through the activation of the immune system.

A known method of treatment (Copyright certificate 1263246, MKI: A61K 6/00, publ. 1986), in which, after anesthesia, the treatment of the oral mucosa is carried out sequentially with a 0.3% aqueous solution of potassium chloride with redox potential (+1000) - (+1100) mV, and then with the redox potential (-400) - (- 500) mV.

The disadvantage of this method of treatment is that the drugs used do not provide a stable remission.

There is a method of treating acute herpetic stomatitis in children, including chemotherapy and immunotherapy (Abstract of the dissertation by Ph.D. Savichuk N.O.Tymic immunomodulators in the treatment of herpetic stomatitis in children. Kiev Institute for the Advancement of Doctors. - Kiev, 1992, 1-20 from.).

The range of antiviral drugs that have sufficient antiherpetic activity and are approved for the treatment of children is limited. This is acyclovir, the side effects of which are the formation of resistant strains of the herpes simplex virus (HSV) and the absence of an anti-relapse effect, and alpizarin. Immunocorrective therapy is mainly represented by thymalin, levamisole, antiherpetic immunoglobulins. The disadvantage of using thymalin in treatment is its low therapeutic effect in relieving symptoms of general toxicosis in children, and about 25 side effects have been established in levamisole. Antiherpetic immunoglobulins (PGIG), as biologics, contain many antigenic substances, toxins, which can also cause unwanted reactions.

A known method for the treatment of herpetic stomatitis, including cooling the foci of lesions of the oral mucosa and medication. The cooling of lesions of the mucous membrane of the oral cavity is carried out by rolling a roller of permeable-porous titanium nickelide impregnated with liquid nitrogen on them, without pressing, in a reciprocating mode, for 2-3 seconds, followed by drug exposure by applying “Acyclovir ointment to these foci” "(RF application for invention 2007135618, IPC A61C 17/36 publ. 03/27/2009)

A known method of treating recurrent herpetic stomatitis complicated by somatoform pain disorder (RF application No. 2005131643, IPC A61K 31/00, publ. 04/20/2005), including specific antiviral therapy, vitamins C and group B, analgesics, interferon inducers, immunocorrective therapy , local treatment with antiviral ointments, antiseptics and painkillers, physiotherapy with a helium-neon laser, desensitizing agents, antiherpetic vaccine, sodium thiosulfate. In addition, from the first day of exacerbation, the treatment is supplemented with 0.1 mg fentanyl IM once a day for 5 days, an inhaled antibiotic Bioparox 4 breaths 4 times a day for 10 days is prescribed, at the same time rinse the mouth with a solution of levamisole prepared immediately before use 2-3 times a day for 10 days, appoint tianeptine before meals 12.5 mg 3 times a day for 10 days, 12.5 mg 2 times a day for 10 days and 12.5 mg once a day for 10 days, on the 10th day from the moment of exacerbation, a sip is prescribed they are 10.0 mg 1 time per day for 10 days i / m, at the same time they are prescribed a 20% solution of levocarnitine 1 teaspoon 3 times a day for 2 weeks and rinsing the mouth with 10% ASD-2F solution prepared immediately before use 3 times a day for 10 days, in addition to preventing the occurrence of long-term non-healing ulcers, Ayurvedic drug Chavanprash is prescribed inside, which is absorbed for 2-3 minutes, 1 teaspoon in the morning 15 minutes before meals for 108 days, then 1 teaspoon in the morning 15 minutes before eating from the new moon to the full olunia for 1 year, throughout the entire period of treatment, use the carnations "Carnation" and "Basil", alternating them. A solution of levamisole for rinsing the oral cavity is prepared by adding 10.0 mg of levamisole in 10 ml of boiled water, and a 10% solution of ASD-2F for rinsing the oral cavity is prepared by adding 10.0 ml of a 100% solution of ASD-2F in 100 , 0 ml of boiled water.

A disadvantage of the known methods of treating acute herpetic stomatitis in children described above is the length of treatment.

A known method of treating acute herpetic stomatitis in children, based on the use of antiviral and immunomodulating drugs (RF patent No. 2190414, IPC ⁷ A61K 33/18, A61K 35/14, A61K 9/00, A61K 6/02, published on 10/10/2002 g .). Individual treatment is carried out locally, depending on the ratio in the cytological smear of healthy and damaged cells: at the beginning of the disease, when there are more damaged cells than healthy cells, 5% anesthesin emulsion, iodinol, 2% alpizarin ointment are prescribed on the lesion site, as a general antiviral drug - tablets of alpizarin and an immunological drug - viferon suppositories, if the smear contains the ratio of damaged and healthy cells 1 ± 0.17 to 1.5 ± 0.21, solcoseryl jelly is added to the treatment, with the corresponding When 1 ± 0.12 to 5 ± 0.17 is prescribed, only solcoseryl jelly is prescribed, in the absence of damaged cells in the smear, local treatment is stopped, when the restoration of the structure of epithelial cells is confirmed in the smear, adaptogens are prescribed inside - Rhodiola rosea extract and Melissa infusion in age-related dosages.

However, this method is difficult to implement, requires qualified medical personnel for periodic microscopic analysis of smear samples for the ratio of damaged and healthy cells (on days 3, 6, 9, 12), and also has a long treatment period.

The closest analogue (prototype) is a method of treating acute herpetic stomatitis in children, based on the use of an immunomodulator of cycloferon in tablets of 0.15 g 1 time per day according to the scheme for 1, 2, 4, 6, 8, 11 and 14 days from the start treatment, as well as for local treatment was used ointment acyclovir 5% 5 times a day (after 4 hours) for 5 days (S.Yu. Strakhova and LN Drobotko. - Acute herpetic stomatitis in children. // Russian Journal Dentistry ”No. 1, 2009. - p.26-29).

The disadvantage of the prototype method is the long term treatment of acute herpetic stomatitis in children.

The technical result of the invention is to reduce the treatment of the disease.

The specified technical result is achieved by the fact that in the method of treating acute herpetic stomatitis in children, including oral administration of an antiviral agent and topical application of an antiviral drug in ointment, according to the invention, Reaferon EU-Lipint obtained by incorporating recombinant alpha is used as an antiviral agent -2b interferon in liposomes, which is administered orally at a dose of 250,000 ME 2 times a day for 3 days, and as an antiviral drug in ointment For local application, Infagel ointment based on recombinant human interferon alfa-2b is used, which is applied in a thin layer to the affected mucous membranes of the oral cavity 2 times a day for 5 days.

Infagel, gel for local and external use is made by Closed Joint-Stock Company Vector-Medica. 1 g of gel contains: the active substance of interferon alpha-2b recombinant 10000 ME; excipients: aluminum hydroxide - 57.8 mg; polyvinyl alcohol - from 17.5 mg; purified water - up to 1 g.

Therapeutic indications: treatment of herpetic lesions of the skin and mucous membranes - simple and herpes zoster, recurrent herpes of the face, genitalia, gingivitis, herpetic stomatitis. Reaferon-EU-Lipint ^® is a human recombinant interferon alpha-2b in the form of a lyophilisate for the preparation of an oral suspension with an activity of 250,000 ME, manufactured by Vector-Medica Closed Joint-Stock Company.

Table 1 Characteristics of the drug Reaferon-EU-Lipint Ingredients Active substance: Quantity, ME Recombinant human interferon alfa-2b (FSP 42-1182-06) 250000 500,000 1,000,000 Excipients: Amount mg Sodium chloride (FSP 42-0324-1619-01, FSP 42-0474-4119-03) 8.01 8.01 8.01 Sodium phosphate disubstituted 12-aqueous (sodium hydrogen phosphate dodecahydrate) (FS 42-2398-94, GOST 4172-76) 4,52 4,52 4,52 Monosubstituted sodium phosphate 2-aqueous (sodium dihydrogen phosphate dihydrate) (GOST 245-76) 0.56 0.56 0.56 Lipoid C100 (ND 42-12882-03) or lecithin (TU 6-09-10-1844-89) 41.18 41.18 41.18 Cholesterol (TU 6-09-10-1780-86, USP 26) 4,53 4,53 4.53 Vitamin E-acetate (alpha-tocopherol acetate) (FS 42-1522-98, ND 42-6027-02) 0.56 0.56 0.56 Lactose (GF X, issue 2.) 91.34 91.34 91.34

Table 1 shows the qualitative and quantitative characteristics of the liposomal preparation Reaferon-EU-Lipint.

Example 1. A method of treating acute herpetic stomatitis in children. A method of treating acute herpetic stomatitis in children includes oral administration of an antiviral agent and topical application of an antiviral drug in ointment form. As an antiviral agent, Reaferon EU-Lipint is used, obtained by incorporating recombinant alpha-2b interferon into liposomes, which is administered orally at a dose of 250,000 ME 2 times a day for 3 days, and as an antiviral drug in ointment form for topical application use Infagel ointment based on recombinant human interferon alpha-2b, which is applied in a thin layer to the affected mucous membranes of the oral cavity 2 times a day for 5 days.

Example 2. The results of clinical studies of the proposed method

The study was conducted on the basis of the Department of Pediatric Dentistry of the Altai State Medical University (Barnaul) in 2005-2006. A clinical study was conducted of Reaferon-EU-Lipint and Infagel preparations, which are forms of recombinant interferon alpha-2b (manufactured by Vector-Medica CJSC) in the complex treatment of acute herpetic stomatitis and relapses of chronic herpetic stomatitis in children, as well as the possibility of preventing relapse chronic herpetic stomatitis.

Under the supervision were 80 children with CHD and relapse of mild and moderate severe CRHC and 40 children with HRHC in remission (a total of 120 patients). Age ranged from 3 to 7 years. Child monitoring continued for 1 year. The duration of the disease with HRGS ranged from 4 months to 5 years, the number of relapses from 2 to 7. Among 80 children with CHD and recurrence of HRGS, two groups of the same severity of clinical symptoms were distinguished. The main group consisted of 60 children, the control - 20 (table 2).

The dynamics of the course of the disease was studied in detail using standard clinical and biomicroscopic studies. The etiology was determined according to the study of antigens in scrapings of the epithelium of the oral mucosa by fluorescent antibodies (MFA) or PCR and enzyme-linked immunosorbent assay (ELISA), determining the level of serum Ig M and Ig G, as well as bacterial culture from the mucous membrane on the flora and sensitivity.

In the main group, HSV-1 antigens were found in 39 children (in 65% of cases). Antibodies to HSV-1 were found in various titers from 1: 200 to 1: 6400 in all patients. A similar picture was observed in the control group: antigens for HSV-1 were present in 12 patients (60%), antibodies to HSV-1 were also found in all in different titers.

40 children with HRGS in remission were also divided into 2 groups: 25 children in the main group and 15 in the control group (table 1). In both groups, HSV-1 antigens were not determined. Antibodies to HSV-1 were found in various titers from 1: 100 to 1: 3200 in all patients.

table 2 The distribution of children in groups Children with OGS and recurrence of HRGS (80 children) Children with HRGS in remission (40 children) Groups 1 (main) 2 (control) 3 (main) 4 (control) The number of children in the group 60 twenty 25 fifteen

All patients received therapy, including diet, heavy drinking, desensitizing therapy, multivitamins, according to indications, antipyretic and analgesic drugs.

As an antiviral and immunomodulating drug, children of the 1st (main) group received Reaferon-EU-Lipint. Reaferon-EC-Lipint, a preparation of recombinant interferon alfa-2b, is a lyophilizate for the preparation of an oral solution. The drug was taken at 250,000 ME 2 times a day 30 minutes before meals for 3 days. Immediately before use, the lyophilized powder was diluted with distilled or boiled water. Locally affected areas of the oral mucosa of children of the 1st group were smeared with Infagel. Infagel - gel for local and external use based on recombinant interferon alpha-2b also has antiviral and local immunomodulating activity. When applied, the gel forms a film, which makes it sufficient to use Infagel 2 times a day.

Children of the 2nd (control) group received an immunomodulator cycloferon in tablets of 0.15 g 1 time per day according to the scheme for 1, 2, 4, 6, 8, 11 and 14 days from the start of treatment. For local treatment in children of group 2, ointment acyclovir 5% was used 5 times a day (after 4 hours) for 5 days.

Table 3 Treatment of children with OGS and recurrence of HRGS 1 group (main) 60 children 2 group (control) 20 children A drug Route of administration A drug Route of administration Reaferon-EU-Lipint 250000 ME Inside 2 times a day 30 minutes before meals for 3 days Cycloferon, tab. 0.15 Inside 1 time per day for 1,2, 4, 6, 8, 11, 14 days from the start of treatment Infagel, gel for local and external use, 10,000 IU / g Locally lubricate the affected areas of the oral mucosa 2 times a day for 5 days Acyclovir, ointment 5% Locally lubricate the affected areas of the oral mucosa 5 times a day for 5 days Solcoseryl Dental Adhesive Paste According to indications, topically lubricate the affected areas of the mucous membrane 3-5 times a day after the end of the course of using Infagel Solcoseryl Dental Adhesive Paste According to indications, topically lubricate the affected areas of the mucous membrane 3-5 times a day after the end of the course of use of Acyclovir Diazolin, tab. 0.05 Inside 2 times a day for 5 days Diazolin, tab. 0.05 Inside 2 times a day for 5 days Paracetamol, solution, tablets Inside according to indications Paracetamol, solution, tablets Inside according to indications Multivitamins Inside Multivitamins Inside Diet, heavy drinking

Results. The criteria for evaluating the effectiveness of treatment were a decrease in the inflammatory response; the disappearance of pain; the onset of epithelialization of the mucous membrane; resorption of exudate. In this case, it was considered the epithelization of the elements of the lesion of the oral mucosa without complete cure of the child from acute herpetic stomatitis, the duration of which is determined not only by the end of the epithelization of the elements of the lesion, but also by the duration of gingivitis and lymphadenitis, as well as deviations in the general well-being of the child.

The results obtained indicate that clinical symptoms in the group using interferon preparations are less pronounced; the disappearance of clinical symptoms in the main group occurred on average 2 days earlier than the disappearance of similar symptoms in the control group, depending on the severity of the process on the 3rd day (without the use of interferon preparations - on the 5th day) (table 4). In children of the 1st group, pain sensations disappeared faster, the body temperature decreased (on average - on the second day, in the control group - on the third), and overall health improved. The effectiveness of the drugs was shown in group 1 already on the second day in the case of going to the doctor on the first day of the disease: erosion did not pass into aphthae, the surrounding mucous membrane did not infiltrate. With a later visit to the doctor, there was a transition of erosion into aphthae, but their severity was less than in the control group. In the 2 (control) group, in 4 cases out of 8, when contacting a doctor on the first day of the disease, erosion turned into aphthae.

Table 4 Average recovery time for children Children with OGS and recurrence of HRGS (80 children) Groups 1 (main) 2 (control) The number of children in the group 60 twenty The average recovery period (days) 3.2 ± 0.4 5.1 ± 0.5 * * - P≤0.05, the differences are significant

19 (68%) of 28 children with CHRH did not have a relapse during the year of observation (usually it occurred with an interval of 3-6 months). In 1 child with HRGS, relapse occurred after 8 months (usually after 3-4 months) and had a mild severity.

The experience of using Reaferon-EU-Lipint in combination with the local use of Infagel in the treatment of children aged 3 to 7 years has shown good results. Reaferon-EC-Lipint and Infagel preparations are simple and convenient to use, well tolerated by children. The drugs have a neutral taste and do not irritate the mucous membranes. In no case was the occurrence of allergic or other adverse adverse reactions.

The data in table 4 indicate the advantage of the inclusion of interferon preparations in general therapy for general and local use, the high efficiency of this regimen, confirmed by a significant reduction in the time of epithelization of elements and the recovery of children.

findings

1. Reaferon-EU-Lipint and Infagel preparations have shown high efficiency in the treatment of acute herpetic stomatitis and relapses of chronic recurrent herpetic stomatitis in children, the appointment of these drugs helps to reduce the duration of treatment, improve its results.

2. Reaferon-EU-Lipint and Infagel are well tolerated by patients, do not cause side effects, Infagel does not have a toxic effect on the oral mucosa.

3. The appointment of Reaferon-EU-Lipinta in combination with the local use of Infagel in the complex treatment of herpetic stomatitis and relapses of chronic recurrent herpetic stomatitis in children is safe and can be recommended for wider implementation in clinical practice.

Claims (1)

A method for the treatment of acute herpetic stomatitis in children, including oral administration of an antiviral agent and topical application of an antiviral drug in ointment, characterized in that Reaferon EU-Lipint, obtained by incorporating recombinant alpha-2b interferon into liposomes, is used as an antiviral agent which is administered orally at a dose of 250,000 ME 2 times a day for 3 days, and Infagel ointment is used as an antiviral drug in ointment for topical application and based on recombinant human interferon alpha-2b, which is applied in a thin layer to the affected mucous membranes of the oral cavity 2 times a day for 5 days.