Pharmacological properties of the drug Cycloferon
cycloferon (N-(1-deoxy-d-glucitol-1-yl)-N-methylammonium-10-methyl-carboxylate of acridone - a salt of acridoneacetic acid and N-methylglucamine, a water-soluble synthetic analogue of the natural alkaloid Citrus grandis. Cycloferon is a low-molecular-weight synthesis inducer interferon, the main producers of which are macrophages, T- and B-lymphocytes. Induces high titers of interferon in organs and tissues containing lymphoid elements (spleen, liver, lungs), activates bone marrow stem cells, stimulating the formation of granulocytes. Cycloferon is effective as an immunomodulator for viral diseases, in complex therapy of acute and chronic bacterial infections. Corrects the immune status of the body in immunodeficiency states of various origins and autoimmune diseases. Highly effective in rheumatic and systemic connective tissue diseases, suppressing autoimmune reactions and providing anti-inflammatory and analgesic effects. After parenteral administration, it penetrates quickly into cells and induces the synthesis of early interferons. Maximum activity is achieved after 2–4 hours. About 99% of the administered cycloferon is eliminated unchanged by the kidneys within 24 hours. Penetrates the BBB, leading to the formation of interferons in brain tissue. Does not accumulate with prolonged use. Recently, limited clinical studies have established the high effectiveness of cycloferon for the prevention and treatment of influenza and other acute respiratory viral infections during the epidemic in children and adults, in the treatment of psoriasis, herpes zoster, endometriosis, and diffuse fibrocystic mastopathy. The indications have been expanded and schemes for the use of cycloferon in dermatovenerological practice have been developed - in the treatment of mycoplasmosis, gardnerellosis, syphilis, candidiasis and other mycoses, trichomoniasis, psoriasis, atopic dermatitis, etc. For the emergency prevention of influenza during an epidemic and the treatment of its mild and uncomplicated forms, the following was effective scheme: 5 injections of cycloferon in 1; 2; 4; 6; days 8 (days 1–2 — 10 mg/kg body weight, day 4 — 8 mg/kg, days 6–8 — 6 mg/kg IM 1 time per day); for the treatment of severe and complicated forms of influenza and other acute respiratory viral infections - 10 mg/kg for 2 days, then 6 mg/kg IM or IV in 4 days; 6; 8; 10; 13; 16; 19th and 22nd days of treatment. For post-influenza neuroinfections - 2 ml IV or IM in 1 dose; 2; 4; 6; 8; eleven; 14; 17; 20th and 23rd days of treatment. For secondary recurrent and latent early syphilis (disease duration more than 6 months), a single dose of 0.25 g is used every other day, 10 injections per course of treatment. In the presence of aggravating factors (chronic alcoholism, drug addiction, tuberculosis), a second course of treatment is possible after 1.5–2 months. For trichomoniasis (the duration of the disease is more than 1 year), 2 courses of treatment with cycloferon are carried out: the first course - 5 intramuscular injections of 2 ml of solution, the second course - 10 injections according to the usual regimen. When treating bacterial vaginosis, a course of cycloferon injections (2 ml IM, 8–10 injections) is carried out when the disease lasts more than 6 months. For acute diarrhea of bacterial etiology in children - at a dose of 6–10 mg/kg per 1 dose; 2; 4; 6; 8th days in combination with other types of therapy. For diarrhea of viral origin, therapy with cycloferon in combination with probiotics is advisable. For intestinal dysbiosis, bacterial carriage - at a dose of 6 mg/kg per 1 dose; 2; 4; 6; 8; 10; 13; 16; 19; Day 22 (10 injections) in combination with vitamin therapy, enzyme preparations and probiotics.
Experience with the use of cycloferon in the treatment of human papillomavirus infection
About the article
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RMJ. Mother and Child No. 16 dated July 17, 2009 p. 1035
Category: Gynecology Obstetrics
Authors: Isakov V.A. , Ermolenko D.K. , Goncharov S.B. , Ermolenko K.D.
For quotation:
Isakov V.A., Ermolenko D.K., Goncharov S.B., Ermolenko K.D. Experience with the use of cycloferon in the treatment of human papillomavirus infection. RMJ. Mother and child. 2009;17(16):1035.
Lesions of the skin and mucous membranes caused by human papillomaviruses (HPV) have been known to mankind for a long time. More than 130 types of HPV are distinguished based on the nucleotide sequence and antigenic properties of capsids. The HPV genome contains DNA. HPVs are species and tissue specific. They are capable of infecting squamous epithelial cells and exhibiting replicative activity within them; they are found on the skin, mucous membranes of the oral cavity, conjunctiva, esophagus, bronchi, larynx, rectum, and genitals [14].
Lesions of the skin and mucous membranes caused by human papillomaviruses (HPV) have been known to mankind for a long time. More than 130 types of HPV are distinguished based on the nucleotide sequence and antigenic properties of capsids. The HPV genome contains DNA. HPVs are species and tissue specific. They are capable of infecting squamous epithelial cells and exhibiting replicative activity within them; they are found on the skin, mucous membranes of the oral cavity, conjunctiva, esophagus, bronchi, larynx, rectum, and genitals [14]. At the end of the twentieth century. An unprecedented spread of HPV infection has been noted: it is believed that approximately three quarters of sexually active adults worldwide are infected with HPV at different stages of their lives. In general, at the moment, HPV infection in people of biologically active age is 20–60% [14]. The infection is transmitted primarily through sexual contact, during medical procedures (infection of medical personnel is possible), vertically, during pregnancy and childbirth. The incubation period is 1–6 months, the maximum content of the virus in the affected tissues is detected in the 6th month. Often the result of infection is diseases of the anogenital area: cancer of the cervix, vulva, vagina, perianal area and genital warts. Cervical cancer is the second most common malignant disease in women: more than 500 thousand cases are registered annually in the world. According to WHO forecasts, the number of deaths from cervical cancer will increase to 320 thousand in 2015 and to 435 thousand in 2030 [12]. The average age of patients with carcinoma in situ is 29 years, i.e. It takes approximately 10 years from the time of initial infection to the appearance of severe neoplasia. Invasive cancer is registered at the age of 49 years, when additional changes in immunity occur, leading to invasion and metastasis [14,15]. Papillomaviruses are the only group of viruses that have been proven to induce tumor formation in humans under natural conditions. The combined persistence of HPV with herpes simplex virus-2, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, chlamydia and mycoplasma is unfavorable. Up to 20 million American citizens suffer from genital warts, and HPV is 3 times more common than genital herpes and no less common than gonorrhea [5]. According to the Ministry of Health of the Russian Federation (2001), the frequency of the most common clinical form of HPV - genital warts - is 26 per 100 thousand population, in the USA - 100 per 100 thousand population. An essential feature of HPV is its ability to switch from a non-productive type of infection to a productive type of infection and vice versa. In the first case, the virus replicates synchronously with the cell and does not harm it. In the second case, it quickly multiplies and lyses the cell, releasing a mass of new virions that can infect other cells [14]. It has been shown that HPV can have different effects on the mucosa. Thus, the manifestation of a productive effect is papillomas and condylomas, and the result of a transforming effect can be intraepithelial lesions (dysplasia, invasive cancer). Thus, the conditions for the formation of irreversible neoplasia are [9]: active expression of the E6 and E7 HPV genes; induction of metabolic mechanisms for the conversion of estradiol into 16a-hydroxysterone, which belongs to the category of “aggressive hormones” that cause a long-term effect; induction of multiple chromosomal DNA damage in the infected cell, which completes the process of degeneration. HPV-1 – HPV-4 types were isolated from stratified squamous epithelium. They are associated with the development of vulgar and flat warts of the hands, as well as plantar warts. In most cases, HPV types 6, 11, 13, and 30 are associated with the development of verrucous laryngitis (juvenile laryngeal papillomatosis). The disease is diagnosed more often in children under 5 years of age who are infected perinatally, and is characterized by the appearance of papillomatous growths on the vocal cords, which leads to speech difficulties and air circulation problems in the upper respiratory tract. HPVs have also been isolated from the mucous membranes of the oral cavity. Cases of laryngeal papillomatosis have been described in children born by cesarean section, so cesarean section should not be performed for the sole purpose of preventing HPV infection of the newborn. As shown above, HPV-6, 11 can cause cancer of the larynx and pharynx, while the role of other types of HPV in malignant degeneration of the oral mucosa has not been sufficiently studied. Rare cases of the development of oropharyngeal warts caused by “genital” serotypes HPV-16, 18 have been noted. The presence of the same types of viruses in different localizations of mucosal lesions suggests a single source of infection and the ability of viruses to interact with various receptors on the epithelium of the oral cavity and urogenital tract. We examined 40 women of childbearing age practicing commercial oral-genital sex. Material was collected (scrapings from altered areas of the mucous membranes) from patients with clinical manifestations of HPV infection. Subsequently, all samples were subjected to genetic analysis using polymerase chain reaction (PCR) with primers aimed at identifying the following types of HPV: 16, 18, 31, 33, 50, 59 [3]. HPV-16 was isolated in 52.5%, and HPV-18 – in 27.5% of cases. HPV-31, 50, 59 were detected much less frequently (7.5%) in the samples. HPV-33 was detected in only two women. It should be noted that in 6 patients several serotypes of the virus were recorded simultaneously. Thus, in 2 samples HPV-16 and 18 were isolated, in 3 samples - HPV-16 and 50, in 1 sample - HPV-16, 31 and 39. The studies conducted indicate the significant role of oral-genital contacts in the spread of human papillomavirus infection, including viruses of high oncogenic risk, and may also indirectly indicate an increased risk of developing malignant diseases of the oral cavity and larynx in women who use oral-genital contact [3]. According to Kozlova V.I. et al. (2003) [10], the urogenital tract is most often affected by HPV-6, 11, 16, 18, 31, 35. Based on the ability of HPV to induce neoplastic processes, they are usually divided into low-grade types (types 3, 6, 11, 13, 32 , 34, 40, 41, 42, 43, 44, 51, 61, 72, 73), medium (30, 35, 45, 52, 53, 56, 58) and high (16, 18, 31, 33, 39 , 50, 59, 64, 68, 70) cancer risk [9,10]. Recently, about 20 types of HPV have been associated with cervical cancer (95%). Among them, HPV-16 (50%) and HPV-18 (10%) are most often detected, and therefore women with confirmed HPV infection should undergo an annual examination by a gynecologist with colposcopy, cytological examination of cervical smears, virological and immunological examination. It is believed that in 50% of cases of human papillomavirus infection (PVI), the virus is cleared from a woman’s body within 1 year, and in 85% of cases – within 4 years. In St. Petersburg from 1999 to 2004, from 28 to 34% of the female population aged 20 to 60 years were infected with HPV and high-risk (HPV types 16 and 18) cancer [11]. HPV contributes to the development of cervical cancer in 99.7%, cancer of the vulva, vagina, penis, prostate, testicle - in 10-30%, cancer of the larynx and oral cavity - in 10-30% of cases. In addition to HPV, a number of concomitant factors play a decisive role in the development of oncogenic transformation. First of all, it is necessary to highlight concomitant infectious diseases of the anogenital area, the causative agents of which are often isolated in patients with HPV infection: chlamydia - 62.1%, gonococci - 23.3%, ureaplasma - 16.2%, herpes viruses - 16%, trichomonas - 14.8%. The combination of HPV infection with two infections was detected in 23.3%, with three – in 16.2%, with four – in 8.1% of cases [2,8]. Of great importance in the development of cancer against the background of PVI are social status and living conditions, hormonal levels corresponding to age, gynecological history (risk factors: early onset of sexual activity, frequent change of sexual partners, cervical canal injuries, number of pregnancies and births, anogenital contacts). An important feature of HPV infection is polymorphism, multifocality of damage to the skin and mucous membranes of the genital tract in the form of clinical, subclinical and latent forms [2,6,7]. In St. Petersburg, a system of preventive measures has been proposed aimed at reducing the incidence of virus-related malignant neoplasms in the population. A comprehensive examination program includes cytological methods, testing for viruses (HPV, CMV, EBV, viral hepatitis B and C). Detection of high cancer risk viruses (HPV-16, 18 types) requires the examination to be supplemented with clarifying diagnostic methods: determination of the level of prolactin, prolactin/TSH in the blood, HPV gene testing (ratio of E2-E6 genes), drawing up a patient’s genetic risk map, which will allow us to offer an individual model of strategy and tactics for treatment and monitoring of the patient, as well as to form risk groups for virus-related tumors [11]. Principles of complex treatment of HPV infection. With PVI, as with other chronic diseases with long-term persistence of the virus, immunodeficiency states (IDS) develop due to insufficiency of various parts of the immune system: there is a decrease in T-cell immunity, immunoregulatory index (CD4/CD8), the number of Langerhans cells and immune response of cervical lymphocytes. The functional activity of natural killer (NK) cells and the level of basic serum immunoglobulins are reduced. The content of CEC in the peripheral blood is increased, which correlates with the prevalence and severity of the process [7,12,13]. Due to the imbalance of the immune system, for more successful treatment in the regimen of infection caused by HPV, it is necessary to include, in addition to antiviral (systemic and local), immunocorrective drugs, as well as pathogenetic agents (systemic enzyme therapy, antioxidants, pro- and prebiotics), which alleviate the patient's condition and contribute to more effective use of the drugs used. When PVI is combined with other pathogens, complex treatment is carried out using etiotropic drugs against specific pathogens in standard dosages. It has been shown that modern treatment does not avoid recurrence of PVI in 20–30% of cases [1,2]. It is assumed that the sensitivity of HPV to certain chemotherapy drugs is primarily due to genetically programmed features of the immune response in this pathology. In the process of evolution, a mechanism has emerged in which a viral infection is protected at the molecular level from the systemic effects of the host immunity. In some cases, the reason for the failure of therapy for infection caused by HPV is the use of interferon drugs (IFN), since the E7 oncoprotein causes resistance of infected cells to IFN drugs during treatment [1,12]. Thus, the treatment of PVI remains a rather difficult task, despite a significant arsenal of drugs and treatment methods. Since complete cure is currently impossible to achieve, it is believed that the goal of the treatment procedures should not be to eliminate the pathogen, but to transfer the infection to a stage of stable remission (clinical recovery). In this regard, the following tactics for managing patients with HPV infection are proposed: 1) destruction of papillomatous foci; 2) stimulation of antiviral immunity, i.e. correction of general and local immunity; 3) a combination of these approaches, eliminating factors contributing to relapse of the disease [7,12,13]. Local destruction of foci during the clinical and subclinical course of HPV infection (aimed at removing the surface layer of the epidermis without sanitizing the cells of the basal layer) makes it possible to cure only the area of the epithelium where the infection manifested itself. In the surrounding tissues, a reservoir of HPV remains in an inactive state or an undiagnosed subclinical form, which can cause relapses of the disease. During a five-year observation of patients with cervical infections caused by HPV, progression of the latent stage of papillomavirus infection into a clinical or subclinical form was noted in 21.4% of cases. Moreover, the clinical manifestation of infection occurs in women with persistent HPV against the background of an imbalance in immunity parameters. Adequate immunotherapy helps suppress the activity of HPV and its complete elimination, reducing the frequency of relapses and the risk of developing precancerous diseases and cervical cancer in patients with latent HPV infection [4,6,12]. For genital warts, both sexual partners are treated. It is recommended to abstain from sexual intercourse while taking medications and use barrier contraception for 6 months. after completion of therapy. Experience with the use of Cycloferon in the treatment of HPV infection. Currently, in the treatment of patients with HPV infection, an alternative approach to the treatment of PVI is very promising. With this technique, IFNs have a protective effect, i.e. Interferon inducers (II) are used, among which the domestic drug Cycloferon deserves special attention (NTTF POLYSAN LLC, St. Petersburg). Cycloferon belongs to low-molecular interferon inducers, the acridone class. When Cycloferon is administered, endogenous IFN is formed, which is not antigenic or pyrogenic; the activity of induced IFN is controlled by special regulatory mechanisms, which ensures the absence of side effects inherent in recombinant IFN drugs as a result of their cumulation; Cycloferon also does not have mutagenic, teratogenic, embryotoxic, or carcinogenic effects; Cycloferon does not induce autoimmune processes. The drug has no described side effects, it goes well with traditional therapeutic treatments (antibiotics, vitamins, immunotropic drugs, etc.). Advantages of using Cycloferon: rapid penetration into the blood, low level of binding to serum proteins, high bioavailability in organs, tissues, biological fluids of the body; the predominant method of elimination from the body is through the kidneys (99% of the administered drug) unchanged, within 24 hours [4,5]. After the administration of Cycloferon, a high level of synthesis of IFN-a in tissues and organs containing lymphoid elements is observed for at least 72 hours, while in the blood serum of a normal person the content of high levels of IFN remains for 48 hours. Mechanisms of action of Cycloferon. One of the key parameters when introducing interferon-inducing drugs into the body, which determine the effectiveness of the immune response, is the profile of cytokines - factors that activate the proliferation and differentiation of body cells, controlling the processes of regeneration, angiogenesis and metabolism. The existence of different cytokine profiles provided by Th cells has been established, with the Th1 type of immune response associated with the production of IFN-g, IL-2 and TNF; the Th2 type is characterized by increased production of IL-4,5,6,10 and leads to increased humoral and suppression of cellular immunity [4,5]. Currently, the direct and indirect immunotropic effects of CP are well described. The influence of Cycloferon on nonspecific immune cells: Cycloferon increases the formation of reactive oxygen species by phagocytes, which promotes completed phagocytosis with the elimination of captured pathogens; causes an increase in the level of NK cells in the peripheral blood. The influence of Cycloferon on specific immune cells: 1) an increase in the level of CD4+ and a decrease in CD8+ T-lymphocytes, normalization of the immunoregulatory index even with a single use of Cycloferon; 2) the use of Cycloferon leads to a decrease in the level of B-lymphocytes in the peripheral blood and to an increase in the production of high-affinity antibodies, which reflects its effect on switching the synthesis of immunoglobulin classes in B-cells; induces the synthesis of IFN-
Indications for use of the drug Cycloferon
Prescribed to adults in complex treatment of: HIV infection (stages 2A–3B); neuroinfections (serous tick-borne meningitis, multiple sclerosis, etc.); viral hepatitis A, B, C, herpes and cytomegalovirus infection; with secondary immunodeficiency of various etiologies, including in patients with acute and chronic bacterial and fungal infections, burns, radiation injuries, peptic ulcers; for chlamydial infection (lymphogranuloma venereum, urogenital chlamydia, chlamydial reactive arthritis); rheumatic diseases and systemic connective tissue diseases (rheumatoid arthritis, etc.); for degenerative-dystrophic diseases of the joints (deforming osteoarthritis, etc.). Cycloferon liniment 5% is used for genital herpes, urethritis and balanoposthitis (including candidiasis, gonorrhea, trichomonas, chlamydia), nonspecific bacterial vaginitis, bacterial vaginosis, candidal vaginitis.
Use of the drug Cycloferon
Usually prescribed IM and/or IV 1 time per day, 250 mg of cycloferon per dose; 2; 4; 6; 8; eleven; 14; 17; 20; 23; 26; Day 29 of treatment depending on the nature of the disease. For acute viral hepatitis, a single dose of 0.25 g is prescribed, 10 injections. For a course of treatment - 2.5–5 g. 2–3 repeated courses are carried out with an interval of 10 days. For chronic viral hepatitis - maintenance therapy according to the following scheme: 1 injection (0.25 g) once every 10 days for 6 months. For herpes and cytomegalovirus infection, 10 intramuscular injections of 0.25 g according to the same regimen, per course - 2.5 g. For chronic forms, 2-3 repeated courses are given with an interval of 10-14 days. For recurrent forms of herpetic infection, combination with other antiherpetic drugs is recommended. For neuroinfections, the course of treatment usually consists of 10 intramuscular injections of 0.25 g according to the schedule (2.5 g). Repeated courses of treatment are carried out as needed. For chlamydial infection, 10 injections are usually given. For a course of treatment - 2.5–5 g. It is necessary to repeat the course of treatment after 3–4 weeks in combination with antibiotics. It is most effective to prescribe antibiotics after the second injection of cycloferon. It is imperative to replace the antibiotic from the 11th day of treatment with cycloferon. For mixed infection, intravenous administration of cycloferon is recommended. For HIV infection, the recommended treatment regimen with cycloferon is 10 injections of 0.5 g each. The first 3 injections are 0.5 g IV, then 0.25 g IM. Repeated courses - every 3 months. For immunodeficiency conditions - 10 intramuscular injections of 0.25 g each, then a course of maintenance therapy - 1 injection of 0.25 g once every 10 days for 4-6 months. For rheumatic diseases and systemic connective tissue diseases, 4 courses of therapy of 5 intramuscular injections (1.25 g) are prescribed with an interval of 10–14 days. For degenerative-dystrophic diseases of the joints, 2 courses of therapy are prescribed, 5 intramuscular injections of 0.25 g (total 1.25 g per course) with a break of 10–14 days. Tablets are taken orally 30 minutes before meals without chewing in a dose of 0.3–0.6 g 1 time per day according to the basic regimen for 1; 2; 4; 6; 8; eleven; 14; 17; 20; 23; 26; 29th day depending on the disease. Liniment is used for intraurethral or intravaginal instillations.
Results and discussion
The main group included 20 patients (7 men and 13 women) aged from 18 to 65 years with a clinical picture of recurrent genital herpes (Table 2). The clinical course of genital GVI in patients of the main group was characterized by a high frequency of exacerbations (up to 1 time in 1-1.5 months), pronounced local symptoms of exacerbation (itching, burning, pain in the affected area). The comparison group consisted of 20 patients with a similar form of GVI, comparable in gender, age and nature of the disease. Over the past 3-6 months, more than 50% of patients included in the study used only local therapy (ointment with acyclovir, interferon, antiseptic solutions) for herpetic lesions during relapse.
Table 2. Characteristics of patients included in the study
All patients participating in the study complained of the appearance of local hyperemia, edema, vesicular or erosive rashes, accompanied by itching, burning, and pain. Before treatment, all patients were examined to identify the type of HSV (1st or 2nd) using the polymerase chain reaction method. A positive result was obtained in 100% of cases. Approximately 1/3 of patients (27.5-37.5%) had symptoms of general intoxication during an exacerbation (headache, low-grade fever, weakness). In 45-50% of patients there was pain along the affected nerves (Table 3).
Table 3. Frequency of registration of GVI symptoms before treatment, abs. (%)
During the treatment of patients with the genital form of CHVI with Valvir
the duration of relapse and the period of complete epithelization decreased on average from 6.4 to 3.8 days, which is significantly different from similar indicators in patients who were prescribed acyclovir (
p
<0.05).
More effective relief of local symptoms (itching, pain, burning) was also noted. The duration of local symptoms in people with exacerbation of genital herpes who took Valvir
was 2.5±0.3 days, while in the group of patients taking acyclovir it was 3.9±0.2 days (
p
<0.05).
There was a reduction in the period of onset of epithelization of herpetic lesions in patients treated with Valvir
to 1.9 days (
p
<0.05 compared to the indicators of the group of patients taking acyclovir) (Table 4).
Table 4. Efficacy of the study regimen of Valvir, days Note.
*—differences are significant compared to the comparison group (p<0.05). It is well known that exacerbation of CHRGVI causes physical pain, discomfort in the affected area and, as a consequence, psychological stress of the patient. Significant reduction in the period of epithelization (complete healing) from 6.4 to 3.8 days while taking valacyclovir ( Valvira
) at a dose of 500 mg 2 times a day made it possible to reduce the severity of local symptoms of relapse and improve the psychological background in patients during an exacerbation of herpes simplex.
When treated with acyclovir, these indicators change less significantly from 6.7 to 4.6 days, which constitutes a significantly longer period of physical and psychological discomfort in the examined individuals during relapse of infection. A positive point is a significant reduction in the duration of local symptoms (itching, pain, burning) to 2.5 days when taking valacyclovir ( Valvira
) (
p
<0.05 versus acyclovir).
In addition, some patients taking valacyclovir ( Valvir
) noted a weakening of local symptoms after the 1st day of taking the drug, while for patients taking acyclovir, this occurs on the 3rd day of taking the drug.
Rapid relief of the symptoms of the disease significantly increases patient satisfaction from the treatment, therefore, the relief of clinical manifestations and symptoms of relapse of HSV when taking valacyclovir ( Valvira
) allows increasing patient adherence to therapy at the time of relapse.
Also, patients taking Valvir
strictly followed the doctor’s recommendations and did not miss doses of the drug, while patients taking acyclovir took the drug irregularly, starting from the 3-4th day of use.
Thus, adherence to treatment and, consequently, its effectiveness in patients in the Valvira
was higher.
During the study, there were no adverse events associated with the administration of the drug Valvir.
requiring interruption or cessation of therapy. Most patients rated the drug's tolerability as “good” or “very good.”
Thus, Valvir
showed good tolerability in patients with CHVI.
The clinical effectiveness of Valvir
in the form of a pronounced reduction in the duration of local symptoms of relapse
.
