Tiloron-sz 125 mg 6 pcs. film-coated tablets

Tiloron-sz 125 mg 6 pcs. film-coated tablets

Composition and release form Tiloron-sz 125 mg 6 pcs. film-coated tablets

One film-coated tablet contains:

• active ingredient: tilorone dihydrochloride - 125 mg;
• excipients (core): microcrystalline cellulose - 105.0 mg; potato starch - 46.0 mg; hypromellose (hydroxypropyl methylcellulose) -4.0 mg, hyprolose (hydroxypropylcellulose) -17.0 mg; magnesium stearate - 3.0 mg; excipients (shell): Opa-dry II 85F220184 - 9.0 mg (macrogol (polyethylene glycol) 3350 - 2.7890 mg; talc - 1.1806 mg; titanium dioxide E 171 - 1.1874 mg; dye-based aluminum varnish sunset yellow E 110 - 1.3315 mg; iron oxide yellow E 172 - 1.1800 mg, indigo carmine dye E 132 - 1.3315 mg).

Film-coated tablets, 125 mg. 6 or 10 tablets in a blister pack made of PVC film and aluminum foil. 20 tablets in a polymer jar made of low-density polyethylene with a lid made of high-density polyethylene or in a polymer bottle made of low-density polyethylene with a lid made of high-density polyethylene. Each jar, bottle, 1 blister pack of 6 tablets or 1 blister pack of 10 tablets, along with instructions for use, is placed in a cardboard box.

Description of the dosage form

Film-coated tablets.

Characteristic

The tablets are round, biconvex, orange film-coated. In a cross-section, the core of the tablet is orange with minor white inclusions.

Directions for use and doses

Tilorone is taken orally after meals. For the treatment of influenza and other acute respiratory viral infections - 125 mg per day for the first 2 days of treatment, then 125 mg after 48 hours. Per course - 750 mg (6 tablets). For the prevention of influenza and other acute respiratory viral infections - 125 mg once a week for 6 weeks. Per course - 750 mg (6 tablets). For the treatment of herpes infection - the first two days, 125 mg, then after 48 hours, 125 mg. The course dose is 1.25 - 2.5 g (10-20 tablets). When treating influenza and other acute respiratory viral infections, if symptoms of the disease persist for more than 4 days, you should consult a doctor.

Pharmacokinetics

After oral administration, it is quickly absorbed from the gastrointestinal tract. Bioavailability - 60%. About 80% of the drug binds to plasma proteins. The drug is excreted almost unchanged through the intestines (70%) and through the kidneys (9%). The half-life (T1/2) is 48 hours. The drug does not undergo biotransformation and does not accumulate in the body.

Indications for use Tiloron-sz 125 mg 6 pcs. film-coated tablets

• treatment of influenza and other acute respiratory viral infections;
• treatment of herpes infection;
• prevention of influenza and other acute respiratory viral infections in adults.

Contraindications

• hypersensitivity to tilorone or any other component of the drug;
• pregnancy and breastfeeding period;
• children's age (up to 18 years).

Application of Tiloron-sz 125 mg 6 pcs. film-coated tablets during pregnancy and breastfeeding

The drug is contraindicated during pregnancy. If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Overdose

Cases of drug overdose are unknown.

Side effects Tiloron-sz 125 mg 6 pcs. film-coated tablets

Allergic reactions, dyspepsia, short-term chills are possible. If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Drug interactions

Compatible with antibiotics and drugs for traditional treatment of viral and bacterial diseases. No clinically significant interaction of tilorone with antibiotics and traditional treatments for viral and bacterial diseases has been identified.

Tiloron as a drug of choice for the prevention and treatment of acute respiratory viral infections

It is difficult to overestimate the medical and social significance of acute respiratory viral infections (ARVI), which not only lead in the structure of population morbidity, but also provoke the occurrence of secondary bacterial infections (pneumonia, otitis, etc.) and exacerbation of chronic pulmonary diseases (asthma, chronic obstructive pulmonary disease etc.) [1–4]. At the same time, only for influenza viruses, out of more than two hundred pathogens of acute respiratory viral infections, preventive vaccines have been developed and are widely used. According to recent systemic reviews and meta-analyses, the effectiveness of specific immunoprophylaxis for influenza varies significantly from season to season, up to complete absence, which is associated with the high antigenic variability of viruses [5, 6]. The only group of antiviral chemotherapy drugs, the use of which, taking into account the sensitivity of influenza pathogens circulating in recent years to them, has been recognized as rational by the world's leading experts, are neuraminidase inhibitors. However, the degree of their effectiveness remains the subject of debate, especially with regard to the development of complications of this disease [7–9]. In addition, the widespread use of oseltavimir and zanamivir inevitably leads to the selection and expansion of resistant strains of influenza viruses, including those nomenclature identified as A (H1N1)pdm2009, which are already being identified among patients [10]. With regard to many other acute respiratory viral infections, in particular respiratory syncytial, rhino-, corona- and metapneumovirus infections, as well as parainfluenza, even in the most developed countries of the world, there are no effective vaccines and antiviral drugs introduced into clinical practice. The main unanswered challenges facing practitioners and developers of means for the specific prevention and treatment of viral respiratory tract infections were the subject of a recent detailed review [11]. The unattainability of effective control of the seasonal incidence of ARVI using vaccination and etiotropic chemotherapy indicates the need to use drugs that affect the most universal innate mechanisms of antiviral defense at the stages of seasonal/emergency prevention and treatment of these diseases [12].

The central link of the antiviral immune response to the invasion of ARVI pathogens are interferons (IFNs). If type II IFN (IFN-γ) mainly activates adaptive cellular responses against virus-infected cells, then type I (IFN-α/β, etc.) and type III (IFN-λ) IFNs provide an innate antiviral response, inducing the expression more than 300 so-called IFN-stimulated genes (ISGs), many of whose products have direct or indirect antiviral activity [13–15]. It is important that these products block all key stages of the life cycle of respiratory viruses, from their penetration into the cell to the budding/release of daughter virions (Table 1). In addition, type I IFN potentiates adaptive cellular antiviral responses [13].

During the evolutionary arms race with improving anti-infective response mechanisms, many ARVI pathogens have acquired the ability to suppress innate defense mechanisms, including the production and biological function of type I IFN. The key molecular mechanisms of the immunosuppressive effects of influenza viruses, parainfluenza, respiratory syncytial virus and some other respiratory tract pathogens have been revealed (Fig. 1).

The above indicates the need to correct disorders of innate defense caused by respiratory viruses, in particular, defects in the IFN system.

However, the role of IFN types I and III in ARVI is ambiguous, and the function of these cytokines is not limited to antiviral protection [11]. It has been proven that excess production of IFN types I and III is one of the main factors in the development of secondary bacterial infections, including pneumococcal pneumonia [3], and virus-induced exacerbations of asthma [18]. For this reason, the objectives of immunocorrective therapy at different stages of viral respiratory tract infection differ significantly.

When the virus enters the body and in the first hours of clinical manifestations of ARVI, a rational strategy seems to be to replenish the insufficient/suppressed production of type I IFN through the exogenous administration of these cytokines or stimulation of their production. On the contrary, at the peak of inflammatory manifestations and in the late stages of viral infection, when, despite the immunosuppressive properties of pathogens, a high level of production of IFN and some other proinflammatory cytokines becomes a factor of damage and the development of complications, the goal of immunomodulation is to suppress the production of these endogenous phlogogenic mediators.

The expediency of temporary suppression of excess production of endogenous mediators of damage to the macroorganism in the acute phase of diseases has been repeatedly emphasized by us [19–22] and is no longer a matter of debate.

The possibility of using tilorone (2,7-bis-[2-(diethylamino)ethoxy]fluoren-9-one) dihydrochloride - the world's first and, perhaps, the most studied oral synthetic IFN inducer [23] - as a universal immunocorrector, which, depending on depending on the mode of administration, the initial state of the macroorganism, the stage of the infectious process, it has multidirectional effects on the production of IFN and other proinflammatory cytokines, discussed earlier [11]. These properties allow tilorone to shift the balance of damage and intensity of the immune response to a zone favorable for the body, in which the likelihood of developing severe forms of ARVI and their complications is minimized or at least significantly reduced (Fig. 2).

In this regard, described back in the 1970s. the ability of tilorone, with daily repeated administrations, to cause a reversible state of hyporesponsiveness, in which further stimulation of cytokine production does not occur, is by no means a negative quality, as some experts believed 30–40 years ago [24], but, on the contrary, a very useful property when using this drug at the peak of the inflammatory manifestations of ARVI.

Obviously, the effectiveness of tilorone in adults and children as a treatment for influenza and other acute respiratory viral infections, confirmed in a series of clinical studies, is largely associated with a temporary decrease in the excess production of IFN and other pro-inflammatory substances. It is important that this immunomodulator, when used therapeutically, not only reduced the duration and severity of the main symptoms of viral respiratory tract infections, but also reduced the frequency and severity of complications of these diseases [25].

No less pronounced is the ability of tilorone to prevent the occurrence of ARVI when taken prophylactically. In this case, the effect of the drug is due to its classification property of inducing the production of IFN types I and II and a number of other cytokines that provide innate antiviral protection and stimulate cellular adaptive immune responses against virus-infected cells.

The high preventive effectiveness of Lavomax, which includes tilorone dihydrochloride as the active ingredient, has been described in workers of a large medical institution (Moscow Research Oncology Institute named after P. A. Herzen), who are at high risk of ARVI, during a period of high seasonal morbidity. The use of Lavomax 125 mg per os once a week for 6 weeks led to a fourfold reduction in the incidence and a fivefold reduction in the average duration of ARVI during the period of drug administration and two weeks of additional observation in comparison with the same size and otherwise comparable control group (Table 2). Among the sick in both groups, the predominant pathogens were parainfluenza viruses and adenoviruses, and during this period in Moscow, in addition to these pathogens, respiratory syncytial virus was a common finding in ARVI (data from Rospotrebnadzor), which was also detected in one participant in the trial. These data indicate a wide range of preventive effects of tilorone against respiratory viruses. Two cases of adverse events were reported during the study. In one case, for each dose of the drug, the subject had loose stools 2–3 times during the first day. These manifestations did not require discontinuation of the IFN inducer. In another case, a study participant was diagnosed with itchy skin rashes, which intensified after the second dose of Lavomax and led to discontinuation of the drug [26].

From December 2006 to May 2007, at the Regional Clinical Hospital of Tula and the City Clinic of Novomoskovsk, the preventive effect of Lavomax was studied in comparison with the effect of subunit influenza vaccines (Grippol, Influvac). Study participants were observed for 6 weeks of use of the drug according to the above regimen and another 12 additional weeks. Taking tilorone by healthy volunteers (n = 340) led to an eightfold reduction in the incidence of acute respiratory viral infections (Fig. 3) and a reduction of more than one third in the average duration of a case of respiratory infection (Fig. 4) in comparison with the control group (n = 260), whose participants did not receive specific or nonspecific preventive agents. At the same time, the preventive effectiveness of the IFN inducer against influenza-like diseases with a laboratory-unverified pathogen was comparable to that registered in a group of volunteers (n = 340), who were exposed to anti-influenza immunization 2 weeks to 9 months before inclusion in the study. The use of Lavomax in a limited group of study participants (n = 40) who were vaccinated with Grippol or Influvac did not reveal the synergism of these specific and nonspecific immunoprophylaxis in reducing the incidence and average duration of ARVI, which can partly be explained by the small size of this group.

During this experience with Lavomax, no adverse events were recorded.

Respiratory pathogens were not verified in this work. However, given the fact that influenza vaccines were highly effective among participants, it can be assumed that the incidence of acute respiratory viral infections in individuals included in the study during the observation period was largely associated with influenza viruses. This can be considered as an argument in support of the thesis about the ability of Lavomax to prevent influenza.

Conducted at the Research Institute of Virology named after. D.I. Ivanovsky studied the effect of Lavomax on the reproduction of influenza type A pathogens (A/Aichi 1/68 (H3N2) and A(H1N1)pdm09) and respiratory syncytial virus in cultures of cells sensitive to these pathogens (dog kidney cells MDCK and human epithelioid cells HEp-2) revealed a direct antiviral effect of the drug. A detailed description of the methodology of this study and its results will be the subject of a separate publication; within the framework of this message, only data regarding the suppression of viral reproduction when Lavomax is added to a cell culture in a “therapeutic” mode (2 hours after infection) are presented. The degree of inhibition of the replication of two strains of influenza pathogens belonging to the two most relevant serosubtypes and respiratory syncytial virus, assessed by a decrease in their infectious titer, was moderate and ranged from 1.5–1.8 Δlg TCID50 (Fig. 5). Moreover, the concentrations at which tilorone exhibited a virostatic effect (5 and 10 μg/ml) not only do not have a cytopathic effect on infected cells, but are also quite achievable in human blood plasma and tissues when the drug is taken orally in a therapeutic dosage. These data correlated with the results of determining the antiviral activity of Lavomax in the same in vitro models using an enzyme-linked immunosorbent assay: suppression of the reproduction of A/Aichi 1/68 (H3N2), A(H1N1)pdm09 and respiratory syncytial virus during the “therapeutic” use of the drug ( 10 µg/ml) were 48.2 ± 5.3, 28.6 ± 6.0 and 45.3 ± 5.7%, respectively.

The contribution of the identified moderate virostatic activity of tilorone to its therapeutic effect in ARVI remains to be clarified.

At the same time, the presented data deserve close attention, since they not only strengthen confidence in the advisability of using this IFN inducer for ARVI, but also reveal opportunities for increasing its clinical effectiveness by improving and personalizing the regimen of use, taking into account the newly discovered antiviral effect. Another starting point for optimizing tactical prescribing regimens and wider use of tilorone in clinical practice may be a new look at the mechanisms of its pharmacological effects from the standpoint of modulating the balance of damage to the body and the severity of the innate immune response.

Thus, tilorone today can be recognized as a drug of choice for the prevention and treatment of acute respiratory viral infections, including influenza, and the properties of the drug discussed in this report indicate prospects for expanding the scope of its clinical use in conditions of a shortage of effective antiviral chemotherapy drugs and vaccines.

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O. V. Kalyuzhin, Doctor of Medical Sciences, Professor

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

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