RU2339377C1 - Method of treatment for genital herpes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly dermato-venereology, and deals with treatment for genital herpes. For this purpose the course is administered as follows: 400 mg acyclovir in oral tablets, 3 times a day during 7 days; additionally 300 mg iodoantipyrine in tablets, 3 times a day for 2 days, then by 200 mg 3 times a day for 2 days, then by 100 mg 3 times a day for 5 days, then by 100 mg once a day for 2 months; at the same time 500000 IU genferon in suppositories vaginally or rectally twice a day for 10 days. 30 days later, repeated genferon treatment course is administered, as above.

EFFECT: provides complex virus-neutralizing, anti-inflammatory, interferon-inducing, immunity-correcting action, followed by recurrences lowering, and without any side effects of the treatment.

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Description

The invention relates to medicine, dermatovenerology, specifically to methods for treating genital herpes.

Genital herpes is widespread, prone to a chronic course and relapse of the disease. The causative agent of the disease is the herpes simplex virus of 1 or 2 types, antibodies to which are detected in 90-99% of the world's population. The introduction of the virus into the body initiates the formation of immunodeficiency, as a result of which the antiviral immunity decreases, conditions for the persistence of the pathogen in the human body are created, which in general leads to relapse of the disease.

In this regard, complex therapy, including the appointment of antiviral chemotherapy drugs, a herpes vaccine, immunomodulators, interferons and interferon inducers, is considered to be a priority in the treatment of genital herpes [1, 2, 3, 4]. Nevertheless, currently known antiherpetic drugs have several disadvantages, including the effect on the latent course of the disease, which determines the frequency and severity of the relapse process [5], as well as the inconvenience of using dosage forms and the complexity of treatment regimens.

So, chemotherapeutic agents (for example, acyclovir), stopping the acute manifestations of herpes virus infection, do not prevent the recurrence of genital herpes. The use of the injectable form of acyclovir is painful and can cause post-injection complications (inflammatory reaction in the injection area, bleeding). Application of acyclovir to the skin in the form of ointment and cream may be accompanied by hyperemia, slight dryness and peeling of the skin.

The use of antiherpetic vaccine is associated with the risk of post-injection complications and the development of allergic reactions.

Interferon therapy has a number of undesirable side effects that limit its use, including: flu-like syndrome, diabetes mellitus, thyroid disease, depression syndrome, autoimmune syndrome (rheumatoid arthritis, lupus syndrome), thrombocytopenic purpura, inhibition of bone marrow hematopoiesis, hemolytic anemia leukopenia, thrombocytopenia, ischemic colitis, melena, sepsis, retinal detachment, hearing loss, impotence [6]. The use of interferon is accompanied not only by side effects, but also by the development of resistance to the doses used, which leads to their subsequent increase, for example, due to the formation of anti-interferon autoantibodies against exogenous recombinant interferon. Another important factor when using recombinant interferons is the high cost of drugs, which makes them inaccessible for widespread use [7].

Among the new generation interferon inducers, cycloferon is widely used to treat genital herpes. Its effectiveness when combined with acyclovir is up to 73% [6].

Closest to the proposed is a method of treatment by prescribing acyclovir, an inducer of endogenous neogen interferon and interferon 2-α-containing preparation of geneferon [8]. However, this method of treatment has several disadvantages. Firstly, a rather complicated pattern of drug use: acyclovir orally 200 mg every 4 hours for 10 days; simultaneously for 10 days, the use of geneferon in the form of rectal (1,000,000 IU) or vaginal (500,000 IU) suppositories 2 times a day; in the subsequent intramuscular injection of a 0.01% solution of neogen for 10 days and then intranasal administration (drops) of neogen 1 time per day for 7 days. Secondly, the need for injection of neogen does not exclude the possibility of post-injection complications. Thirdly, the relapse rate in about 17% in the long term (6-8 months) after treatment.

A new technical task is to increase the effectiveness of the treatment of genital herpes by reducing the frequency of relapses.

To solve the problem in the method of treatment of genital herpes, which consists of pharmacotherapy with the drug acyclovir and genferon, from the first day of treatment, 400 mg acyclovir tablets are administered by mouth 3 times a day for 7 days and additionally 300 mg 3 times a day iodantipirin tablets 2 days, then 200 mg 3 times a day for 2 days, then 100 mg 3 times a day for 5 days, then 100 mg 1 time per day for 2 months and at the same time geneferon suppositories 500,000 IU vaginally or rectally 2 once a day for 10 days, also through 30 days spend a second course of treatment with Genferon according to the above regimen.

The method is as follows. After a diagnosis has been established (complaints, medical history, genital status, cytological examination), 300 mg iodantipirin tablets are prescribed 3 times a day for 2 days, then 200 mg 3 times a day for 2 days, then 100 mg 3 times a day for 5 days then 100 mg once a day for 2 months and at the same time suppositories of geneferon 500,000 IU vaginally or rectally 2 times a day for 10 days with re-appointment of geneferon according to the above regimen after 30 days, and also from the first day of treatment, tablets are prescribed 400 mg acyclovir by mouth 3 times a day in those reading 7 days.

The drug YODANTIPIRIN (1-phenyl-2,3-dimethyl-4-iodopyrazolone) is approved by the Ministry of Health of the Russian Federation for use in medical practice (registration certificate 96/316/2), produced in Russia (NTM company). The therapeutic and prophylactic effect of iodantipyrine in case of viral infections is due to a combination of its anti-inflammatory, virus-neutralizing, interferon-inducing and immunocorrecting activities. Iodantipyrine reduces mast cell degranulation, which prevents the release of various inflammatory mediators, inhibits prostaglandin-synthesizing enzymes, and inhibits the synthesis of arachidonic acid. In addition, iodantipyrine reduces the permeability of membranes, which is important in the process of inhibition of inflammation [9, 10]. One of the energy components of the anti-inflammatory effect is a decrease in the intensity of biological oxidation and inhibition of the associated processes of phospholation and the formation of ATP in mitochondria. The drug inhibits the reproduction of RNA and DNA viruses with the participation of the cell genome. The antiviral effect of iodantipyrine is carried out at the stage of transcription of genetic information and is the result of the formation and excretion of species-specific antiviral inhibitors by human cells [11, 12]. Iodantipyrine is an effective inducer of interferon, has a membrane-stabilizing effect, which also determines the inhibition of the penetration of the virus into the cell. Along with this, iodantipyrine has immunomodulating activity, expressed in the ability to induce the synthesis of virus-neutralizing antibodies, stimulate cellular immunity - mature T-lymphocytes, natural killers, helpers, inducers; inhibits the activity of T-suppressors, modulates cellular and humoral immunities [12, 13].

Indications for the use of iodantipirin are influenza, parainfluenza, acute respiratory viral infections, tick-borne encephalitis, non-polio enteroviruses Koksaki and ECHO, viral vesicular stomatitis, herpes types 1 and 2, hemorrhagic fever, cytomegalovirus infection [11, 12, 14, 15].

Iodantipyrine has low toxicity, does not have mutagenic, embryotoxic, allergenic and immunotoxic properties [13].

Iodantipyrine is available in 100 mg tablets.

The GENERON drug is a combined drug whose action is due to the healing properties of the components (interferon α-2; taurine, anestezin) that make up its composition; approved for use in the Russian Federation (registration number No. P No. 001812/01). It is made in Russia (CJSC BIOCAD).

Gerferon has a local and systemic effect.

Interferon α-2, which is part of the geneferon preparation, has an antiviral, antimicrobial and immunomodulating effect.

Under the influence of interferon α-2, the activity of natural killers, T-helpers, phagocytes, as well as the intensity of differentiation of B-lymphocytes, increases in the body. Activation of leukocytes contained in all layers of the mucous membranes ensures their active participation in the elimination of active pathological foci and ensures the restoration of secretory immunoglobulin A. Interferon α-2 also directly inhibits the replication and transcription of viruses, chlamydia.

Taurine, which is part of geneferon, has regenerative, reparative, membrane, hepatoprotective, antioxidant and anti-inflammatory properties.

Anesthesin, which is part of geneferon, being a local anesthetic, prevents the onset of pain by reducing the permeability of the cell membrane of nerve cells for sodium ions, displacing calcium ions from receptors located on the inner surface of the membrane, leading to blocking of nerve impulses.

With vaginal or rectal use of geneferon, interferon α-2 is absorbed through the mucous membrane, enters the surrounding tissues, into the lymphatic system, providing a systemic effect. The local effect of the drug is due to fixation on the cells of the mucous membrane.

Genferon is used as a complex therapy for infectious and inflammatory diseases of the urogenital tract: genital herpes, chlamydia, ureaplasmosis, mycoplasmosis, recurrent vaginal candidiasis, gardnerellosis, trichomoniasis, papillomavirus infection, bacterial vaginosis, cervical erosion, bervitinitis, cervitis bivitis, cervinitis, cervitis bivitis, cervitis bivitis, cervinitis, cervititis, cervititis, cervititis , urethritis, balanitis, balanoposthitis [8, 16, 17].

Genferon is a drug with minimal manifestation of side effects of exogenous interferonization [16]. The use of the drug is allowed in the second half of pregnancy. However, side effects of geneferon are: allergic reactions in the form of skin rashes and itching, which are reversible and disappear 72 hours after the drug is stopped or the dose is reduced; phenomena that occur with the use of all interferon α-2 inputs, including chills, fever, fatigue, loss of appetite, muscle and headache, joint pain, sweating, and leuko- and thrombocytopenia that occur when high doses of the drug are administered (over 1,000,000 IU daily) [17].

A contraindication to the use of geneferon is intolerance to the components that make up the drug. Relative contraindications are allergic and autoimmune diseases.

The drug Acyclovir - an antiviral agent - a synthetic analogue of thymidine nucleoside. Approved for use in the Russian Federation. It is produced by a number of foreign and domestic companies. In infected cells containing viral thymidine kinase, phospholation and transformation into the active compound, acyclovir triphosphate, occurs. High selectivity and low toxicity to humans are due to the lack of the necessary enzyme for the formation of acyclovir triphosphate in intact cells of the macroorganism. Acyclovir triphosphate, "integrating" into the DNA synthesized by the virus, blocks the reproduction of the virus. The specificity and very high selectivity of the action is also due to its predominant accumulation in cells affected by the herpes virus. Highly active against herpes simplex virus type I and II; chickenpox virus and herpes zoster (Varicella zocter); Einstein-Barr virus. Moderately active against cytomegaloviruses. With herpes, it prevents the formation of new elements of the rash, reduces the likelihood of skin dissemination and visceral complications, accelerates the formation of crusts, and reduces pain in the acute phase of herpes zoster. It has an immunostimulating effect. After oral administration, it is partially absorbed in the intestine, due to low lyophilicity, absorption after oral administration of 200 mg is 20%, however, dose-dependent concentrations are created that are sufficient for the effective treatment of viral diseases. Penetrates through the blood-brain barrier and the placental barrier, excreted in breast milk. It penetrates well into organs and tissues, the concentration in the cerebrospinal fluid is 50% of the level in the blood.

Indications for the use of acyclovir: herpes simplex of the skin and mucous membranes, neonatal herpes infection, eczema, pneumonia, acute primary genital infection (treatment; prevention of relapse in individuals with immunodeficiency); chicken pox; shingles.

A contraindication to the use of acyclovir is hypersensitivity to the components of the drug. A side effect of acyclovir, manifested both with hypersensitivity and with the use of large dosages, are disorders of the nervous system (headache, weakness, dizziness), and the gastrointestinal tract (abdominal pain, nausea, diarrhea) [1, 18].

The properties of the drugs (iodantipyrine, genferon, acyclovir) affect the symptoms of genital herpes caused by the herpes simplex virus of types 1 or 2, revealed on the basis of clinical observations of this category of patients. The regimen of iodantipyrine and geneferon was established on the basis of clinical observations of groups of patients with genital herpes, the regimen of use of acyclovir coincides with the regimen of its use according to the instructions for use of the drug.

Under observation were 62 patients (28 men and 34 women) aged 19 to 39 years old with an established diagnosis of recurrent genital herpes caused by the herpes simplex virus of type 1 or 2. The duration of the disease ranged from 1 year to 3 years. The course of the viral process of genital localization was characterized by exacerbations 3-4 times a year, the duration of which was on average 7-10 days. All patients underwent therapy according to the above scheme.

During observation of patients during and after therapy, good tolerability of the drugs was established. At the same time, the use of drugs did not cause any general (toxicity, dizziness, weakness, chills, allergic rashes) and local (hyperemia, swelling, increased pain) toxic reactions. None of the patients dropped out of the study due to individual drug intolerance.

Conducted therapy has allowed relatively quickly stop the clinical manifestations of exacerbation of the disease. The treatment period was characterized by an early (by the end of the second day after the start of therapy) disappearance of pain, itching and burning. The duration of rashes averaged 4-5 days. On the 10th day in 51 patients (82.3%) of the treatment, according to the polymerase chain reaction, relief of relapse was detected (absence of herpes simplex virus type 1 and 2 in scrapings from the affected areas), and after 6 months. - in 57 (91.9%) patients. In other cases, the causative agent of the disease was detected in the absence of obvious signs of exacerbation of herpetic genital infection.

Within 9 months there were no relapses after treatment in 59 people (95.1%). In other cases, relapses were sporadic and were characterized by minimal clinical manifestations of the disease.

Obviously, the good therapeutic effect of the combination therapy of genital herpes with iodantipyrine, genferon, and acyclovir was associated with normalization of the immune system and the neutralizing activity of the drugs used. So, the study of the parameters of the immune status at the time of initiation of therapy in all patients showed signs of secondary immunodeficiency. At the same time, there was a tendency to a decrease in the number of CD3, CD4 and CD16 lymphocytes in the blood plasma, as well as the value of the immunoregulatory index of CD4 / CD8 against the background of a decrease in the level of CD8 lymphocytes and an increase in the concentration of IgM and IgG. At the end of treatment, immunity indices in 47 patients (75.8% of cases) were almost completely normal.

Clinical example (extract from an outpatient card). Patient P., 29 years old, complained of pain, vesicles and cracks in the external genital area, appearing after menstruation, as well as weakness, malaise, irritability.

Medical history. Sick for 2 years with relapse up to 5 times a year. Over the past 6 months. intervals between relapses decreased to 1.5 months. Periodically received treatment: acyclovir (tablets, cream), alpizarin, methyluracil, cycloferon, panavir. During treatment, the patient experienced discomfort from injection of drugs and low effectiveness of therapy. Recently, against the background of the use of acyclovir, betadine and panavir, relapses occurred with severe pain, weeping in places of rashes, which forced the patient to be absent from work.

Gynecological history. Menses regular, moderate, painless. Sexual life since 20 years. Over the past year - one sexual partner, contraception - a condom. Pregnancy - 0.

Genital status. The external genitalia are formed correctly, the Bartholin glands are without features. In the area of the labia majora, perineum, there are multiple, rounded foci against a hyperemic background, merging with the presence of erosion, cracks, covered with a yellowish coating, sharply painful on palpation. The walls of the vagina are hyperemic, the cervix is cylindrical, clean. The body of the uterus, appendages - without signs of pathology. Discharge - abundant mucous membranes.

A preliminary diagnosis is made: recurrent genital herpes of the external genitalia, severe perineum. According to the results of further examination revealed:

Purity swab:

- vagina: white blood cells - single in the field of vision; squamous epithelium with signs of viral damage. Flora is a small stick; gonococci, trichomonads are absent;

- vulva: white blood cells - 25-30 in the field of view; squamous epithelium in large quantities. Flora is mixed.

Cytological examination: the cervix is an epithelium without features.

Colposcopy: without signs of a pathological process.

Enzyme-linked immunosorbent assay for the presence of total antibodies to syphilis - negative reaction; for herpes simplex virus - a titer of immunoglobulins M in blood serum - 1: 100, a titer of immunoglobulins G in blood serum - 1: 800.

Polymerase chain reaction: herpes simplex virus type 2 was detected.

Diagnosed with recurrent genital herpes of the external genitalia and perineum of a severe degree; subacute vulvitis.

Prescribed treatment: iodantipirin tablets 300 mg 3 times a day for 2 days, then 200 mg 3 times a day for 2 days, then 100 mg 3 times a day for 5 days, then 100 mg 1 time per day for 2 months and at the same time suppositories of geneferon 500000 IU vaginally 2 times a day for 10 days with re-appointment of geneferon according to the above regimen after 30 days. In addition, from the first day of treatment, acyclovir tablets (Synthesis AKO company, Russia) were prescribed 400 mg by mouth 3 times a day for 7 days.

During the treatment period, epithelization of the skin and mucous membranes was completed by the 5th day. The pain in the lesions disappeared by the 3rd day. During the follow-up examination after 14, 30, 40 and 75 days, 6 and 9 months after the start of treatment, no recurrence of the disease was detected. Cytological examination - without features. During the control examination (polymerase chain reaction), the presence of the herpes simplex virus of 1/2 types after 30 and 75 days from the start of treatment was not detected.

This regimen of iodantipirin use is justified by the fact that, according to clinical observations, the use of the drug in a lower dose in the first days of treatment (1-2 tablets per day less than the indicated treatment regimen) did not contribute to the rapid relief of the symptoms of the disease, and the reduction in the time taken to maintain the maintenance dose (from 9 on the 70th day of treatment) was accompanied by recurrence of the disease with a frequency of up to 36-40% of cases. In addition, the use of iodantipirin in large doses in the initial period of treatment (the first 9 days) increases the risk of developing ulcerative lesions of the gastrointestinal tract.

The mode of use of genferon is due to the instructions for use of the drug. The difference is a repeated course of treatment, which reduces the frequency of recurrence of herpes infection. Reducing the period of use of geneferon (up to 5-7 days) did not allow to quickly stop the symptoms of exacerbation of herpetic infection and was accompanied by an increase in relapses up to 23-25% of cases, as well as the preservation of increased sensitivity in places of rashes. The use of genferon with a lower frequency (once a day) is not recommended by the instructions for use of the drug (a decrease in the level of serum interferon 12 hours after the administration of geneferon necessitates its repeated use), and an increase in the frequency of administration (3-4 times a day), or single doses are as effective as when taken twice, and, in addition, increases the frequency of undesirable side effects (sweating, fatigue, allergic reactions).

The mode of use of acyclovir in the proposed method coincides with the mode of its use in the instructions for use of the drug. Given the high effectiveness of the drug exclusively in the acute period of the disease, which is due to its effect only on cells affected by the herpes simplex virus, the longer and higher doses of acyclovir are inappropriate due to the lack of new foci of infection and the possible occurrence of side effects.

The absence in the patent and scientific literature of information on the treatment of genital herpes with the combined use of iodantipyrine, geneferon and acyclovir in the proposed mode indicates the compliance of the claimed technical solution with the criterion of "NEW".

The proposed method for the treatment of genital herpes meets the criterion of "significant difference". The authors found that the regimen of iodantipyrine in combination with geneferon and acyclovir can reduce the recurrence rate and accelerate the relief of symptoms of exacerbation of genital herpes.

The proposed method of treatment meets the criterion of “industrially applicable”, since it successfully passed clinical trials in the clinic of the Department of Dermatovenereology of the Siberian State Medical University, in the MLPMU “Clinic No. 6” and the medical association “Health” in Tomsk.

Thus, the proposed method for the treatment of genital herpes allows you to achieve a persistent clinical effect in patients with genital herpes, namely, to reduce the frequency of relapse of the disease, to reduce the time and severity of the symptoms of the disease during the exacerbation. This, undoubtedly, defines the proposed method of treatment as more effective in comparison with the currently known methods of treatment of genital herpes. In addition, the use of iodantipyrine in combination with genferon and acyclovir in the treatment of genital herpes is well tolerated by patients, does not cause local and systemic reactions, reduces pain, promotes rapid healing and elimination of the pathogen from affected tissues, and also reduces the likelihood of recurrence of the disease. Along with this, good tolerability, a simple application regimen and a convenient way of administering iodantipirin, genferon and acyclovir (tablets), which do not require the presence of medical specialists and avoid post-injection complications, the analgesic effect of genferon, which allows to relieve pain, inflammatory and edematous symptoms in the early stages , the relative cheapness and affordability of acquiring drugs in a network of pharmacies, the manufacture of iodantipyrine, genferon and acyclovir by domestic manufacturers lyayut widely use this method for the treatment of genital herpes in outpatient and inpatient settings.

List of literary sources,

used in compiling the description

1. Samgin M.A., Khaldin A.A. Herpes simplex (dermatological aspects). - M .: MEDpress-inform, 2002 .-- 160 p.

2. Patel R. Progress in meeting today's demands in genital herpes; an overview of current management // J. Infect. Dis. - 2002. V.186, N.15., Suppl. 1: - S. 47-56.

3. Beauman J.G. Genital herpes: a revive // Am. Fam. Physician. - 2005 .-- V.72, N8. - P.1527-1534.

4. Barinsky I.F., Samoilenko I.I., Zaitsev A.V., Makhmudov F.R. A complex method of treatment of chronic recurrent herpes infection // Herpes (Appendix to the "Russian Journal of Skin and Sexually Transmitted Diseases"). - 2006. - No. 1. - S. 43-47.

5. Ershov F.I. Antiherpetic // Russian Journal of Skin and Sexually Transmitted Diseases. The herpes application. - 2006. - No. 1. - S. 5-11.

6. Isakov V.A., Rybalkin S.B., Romantsov M.G. Herpes virus infection: Recommendations for doctors. - SPb., 2006. - 96 p.

7. Ershov F.I. The interferon system is normal and with pathology. - M .: Medicine, 1996 .-- 239 p.

8. Ujuhu V.Yu., Korotky N.G., Borisov I.V. Combined therapy for genital herpes, including Neogen and Genferon // Clinical dermatology and venereology. - 2006. - No. 2. - S. 32-35.

9. Saratikov A.S., Prishchep T.P., Yavorovskaya V.Ya. Anti-inflammatory properties of pyrazolone derivatives. - Tomsk: TSU Publishing House, 1975 .-- 200 p.

10. Saratikov A.S., Sokerin O.L. Therapeutic and prophylactic use of iodantipirin // Materials of the on-site session of the SB RAMS - Novosibirsk, 1996. - P.85-87.

11. Saratikov A.S., Yavorovskaya V.Ya. Iodantipyrine - a means of treatment and prevention of tick-borne encephalitis // Experimental and clinical pharmacology. - 1998. - T. 61. - S. 51-53.

12. Saratikov A.S., Naumova A.V. Yodantipirin - an antiviral drug // 2nd Interregional Pharmaceutical Conference “Siberian Pharmacy at the Turn of the 21st Century”. Conference proceedings. - Novosibirsk, 2000 .-- S.108-110.

13. Report on an experimental study of the harmlessness of iodantipyrine for developing animals / SSMU, Head Saratikov A.S. Tomsk., Publishing house of TSU, 1997 .-- 16 p.

14. Lepekhin A.V., Saratikov A.S., Puchkova N.N., Ratner G.M., Buzhak N.S. Yodantipirin - a new effective tool for the prevention of influenza and other acute respiratory viral infections // Siberian Medical Journal. - 2000. - No. 2. - S. 19-21.

15. Instructions for use of the drug "Iodantipirin." LLC NTM. Russia.

16. Ujuhu V.Yu., Kubylinsky A.A., Tikhomirov A.A. The experience of using Genferon and cryodestruction in the treatment of lesions of the anogenital area with human papillomavirus // Infectious diseases. - 2005. - No. 3. - S.1-3.

17. Instructions for use of the drug Genferon. CJSC BIOCAD. Russia.

18. Instructions for use of the drug Acyclovir. "Synthesis of AKO." Russia.

Claims (1)

A method of treating genital herpes, which consists of pharmacotherapy with acyclovir and geneferon preparations, characterized in that from the first day of treatment, 400 mg acyclovir tablets are administered by mouth 3 times a day for 7 days and additionally 300 mg iodantipirin tablets 3 times a day 2 days, then 200 mg 3 times a day for 2 days, then 100 mg 3 times a day for 5 days, then 100 mg 1 time per day for 2 months and at the same time suppositories of geneferon 500,000 ME vaginally or rectally 2 times per day for 10 days, also after 30 days wire so re-treatment Genferon the above regime.