Experimental use of the antiviral drug "Triazavirin" for the treatment of calves with symptoms of respiratory system damage

. The article discusses the use of antiviral drugs "Ingavirin" and "Triazavirin" in complex therapy for the treatment of calves with symptoms of damage to the respiratory system. The research was conducted on the basis of the Federal State Budgetary Institution of Higher Education "Izhevsk State Agricultural Academy" (Izhevsk State Agricultural Academy). When ingavirin was taken, the clinical condition improved on the eighth day, when triazavirin was taken - on the fifth. The analysis of the average daily weight gain showed that when triazavirin is taken by 6 months of age, the weight gain is 171.97%, which exceeds the indicators of the first group by 28.68%, the control group by 76.67%. Hematological, biochemical, hormonal (TSH, T4, T3.), immunological (IdA, IdM, IgG) indicators were also studied. A comparative analysis of the use of antiviral drugs "Triazavirin" and "Ingavirin" showed that when using triazavirin, the clinical picture of the disease improves at an earlier time.


Introduction
Modern agriculture is characterised by an intensive type of animal exploitation.Various types of disease are already seen in newborn animals, particularly calves.These include parasitic diseases (cryptosporidiosis), viral diseases of the gastrointestinal tract and respiratory organs (adenovirus infection, rota-coronavirus infection, parainfluenza-3, rhinotracheitis, respiratory syncytial infection, viral diarrhoea -mucous membrane disease, etc.) [1][2][3][4][5][6][7][8][9][10][11][12][13][14].Disturbances in the conditions of housing (microclimate) and feeding (lactation) of newborn calves, as well as violations of vaccination of breeding stock (pregnant cows, mother cows) cause immunity failures and the development of diseases.Subsequently, secondary microflora settle and develop in the respiratory and digestive system [4,5,6,9].At this stage, treatment with antibacterial drugs is effective.Consequently, veterinary professionals should aim to cover etiological factors extensively in the treatment of animals.Unfortunately, antiviral drugs are practically not used to treat

Results
Calves with signs of respiratory system damage were selected for the experiment, the preliminary intravital diagnosis being bronchopneumonia.The animals presented with nasal effusions of various nature, sneezing, sniffing, coughing, weakness, oppression, head down, appetite reduced.On examination of the animals, wheezing, shortness of breath, increased body temperature and sweating are noted.On examination, the body temperature averaged 40.6 0 С (m=0.25),pulse -97.6 (m=1.78)beats per minute, respiration -49.7 times per minute (m=3.06).
Calves of the first and second experimental groups received comprehensive treatment with antiviral, antibacterial, sputum draining drugs, as well as symptomatic treatment.
In the first experimental group the calves received the antiviral drug Ingavirin in a dose of 1 capsule per day per head, 7 days, as well as the antibacterial drug Azitronite in a dose of 3 ml intramuscularly once a day, 7 days.By the third day, the calves began to feel better, began to move around the cage actively and eat their feed.On examination, the temperature averaged 39.86 0 С (m=0.88),pulse 110.2 beats per minute (m=5.12),respiration 50.7 times per minute (m=2.63).By the eighth day signs of stabilization appeared -temperature, pulse, breathing within physiological norm, appetite stably good, animals active, no wheezing or coughing, residual effusions from nasal cavity noted.
Second experimental group of calves received antiviral preparation "Triazavirin" at the rate of 1 capsule per day per head, 7 days, as well as antibacterial preparation "Lexoflon" -2 ml once a day, intramuscularly into the middle third of neck, 7 days.Improvement in the condition of the experimental calves was noted by the second day.The animals were active, moved around the cage, and ate feed with appetite.On examination, the average temperature was 39.71 0 С (m=0.43),pulse 98.3 (m=1.83)beats per minute, respiration 50.2 (m=2.53)times per minute.By the fifth day the temperature was normal, breathing was even alveolar, there was no shortness of breath, wheezing or coughing.By the eighth day of the experiment the condition of the animals was stable.
In the third experimental group the calves were not treated.On the second day there was an increased temperature, cough, shortness of breath, wheezing.On examination, the temperature averaged 40.384 0 С (m=0.23),pulse 110.9 (m=2.88)beats per minute, respiration 55 (m=3.02)times per minute.By the fifth day there were no signs of improvement.On the eighth day, the calf's condition was severe.On examination, temperature averaged 40.280C (m=0.25), pulse 111.7 (m=3.56)beats per minute, respiration 58.2 (m=2.15)times per minute.The animals were lethargic, laying down, hardly eating food, breathing heavily, nasal effusion of a purulent nature.After clinical examination on day 8 and completion of the experiment, the animals were treated according to farm-approved therapeutic protocols to prevent mortality.
The average live weight of the calves at birth was 36 kg in the first and 38 kg in the second and third experimental groups.By the age of 3 months, during the period of the disease and in the experiment the average daily gains were 0,589 kg, 0,478 kg, 0,467 kg in groups 1, 2, 3 of experimental group respectively.Three months after treatment and administration of antiviral drug, the average daily gains were 0.844 kg, 0.822 kg, 0.445 kg in groups 1, 2, 3 respectively (Table 2).
In newborn animals in the first month of life, the development of diseases of the digestive and respiratory systems leads to severe disorders not only in these systems, but also in the whole body, and the appearance of complications.The work of the digestive and metabolic systems is disturbed, the supply of oxygen to the body is reduced, the cardiovascular system, immune and endocrine systems are affected, and as a result this affects the fattening and productivity of animals over a long period of time.Timely and effective treatment helps to reduce such abnormalities and stabilise the body.
In the first experimental group after treatment and taking the antiviral drug "Ingavirin" the average daily gain by six months of age was 143.29%, which is 47.99% more than the control figures.In the second experimental group after treatment with the antiviral agent "Triazavirin" average daily gain at six months of age was 171.97%, which was 76.67% more than in the control group and 28.68% more than in the first group.In the third control group, the average daily weight gain at six months of age was 95.3 %.Note: * -P≥0.950,** -P ≥ 0.990, *** -P ≥ 0.999 During the experiment on the use of antiviral drugs for the treatment of calves with respiratory system lesion symptoms, haematological, biochemical, immunological and hormonal data were obtained.
Analysis of haematological parameters revealed in the first experimental group the decrease of leucocytes by 84,79% which corresponds to the average level of physiological indices; in the second group the leucocytes level decreased by 82,44%, and in the third group -by 10,4%.The level of lymphocytes also changed, with a decrease of 46.2% in the first group, 42.95% in the second and 14.8% in the third.Monocytes increased by 157.45%, 44.68%, 77.66% and granulocytes decreased by 13.07%, 40.52% and 40.03% in the first, second and third groups respectively.
In the analysis of the level of erythrocytes, an increase of 38.8% in the first group, 34.1% in the second group and 22.8% in the third group was observed after taking the drugs.Hemoglobin increased by 21.5%, 25.5%, 5.4% in the first, second and third groups respectively.The haematocrit in the first and second experimental groups increased by 11.4% and 14.83%, respectively, and decreased by 3.6% in the third group.The level of platelets increased steadily even in the control group, in the first group by 70.68%, in the second group by 51.98% and in the third group by 2.57% (Table 3).Note: * -P≥0.950,** -P ≥ 0.990, *** -P ≥ 0.999 Analysis of the serum biochemical data of the calves that took part in the experiment showed significant changes in various parameters (Table 4).
Cholesterol and creatinine levels do not change significantly in the groups and remain within the physiological norms.
The levels of AST (aspartate aminotransferase) and ALAT (alanine aminotransferase) increase in the third group by 126.69% and 111.83%, respectively, and exceed the average physiological rates.In the first and second groups the increase is not significant, AST is 31.24%,15.9% and ALAT is 47.84% and 8.83%, respectively.De Ritis coefficient, both before and after the experiment, exceeded the average value in all groups.In the first experimental group the index slightly decreased by 11.2%, in the second group it increased by 6.56% and in the third group by 6.95%.
The level of urea from all the experimental groups, significantly increased in the third group -by 241.16%.
In the first and third experimental groups alkaline phosphatase decreases by 3.45% and 9.4%, respectively, in the second experimental group the alkaline phosphatase increases by 19.9%.
GGTP (gamma-glutamyl transpeptidase) before and after the experiment, in all groups exceeded the average value, in the first group by 77.6%, in the second group by 106.9% and in the third group by 37.9%.
The level of LDH (lactate dehydrogenase) in the experimental groups increases, in the first and second experimental groups is within the norm, and increases by 31.9%, and by 1.84%, respectively.In the third experimental group, the increase in LDH level is significant, amounting to 116.1%, and exceeds the physiological limits.
The iron level does not change significantly between the groups, and remains within the physiological limits.
An increase in serum iron-binding capacity (SIBC) was observed before the experiment.After carrying out of the experiment in the first experimental group increase was noted by 0.58 %, in the second and third decrease by 18.02 % and by 22.5 % accordingly.After the experiment in the first experimental group the level of SIBC exceeds the physiological level, in the second and third groups it decreases to physiologically correct values.
The level of ISC (iron saturation coefficient) does not change significantly in the groups, and remains within the physiological norms.Analysis of hormonal indicators of calves' serum showed a number of changes (Table 5).The level of TH (thyroid hormone) increased after the experiment, in the first group by 123.1%, in the second group by 28.2% and in the third group by 1707.7%.Free thyroxine (T4) after the experiment increased, in the first group by 30.3%, in the second group by 21.7%, in the third experimental group decreased by 21.7%.Total triiodothyronine (T3) after the experiment increased, in the first and second group by 4,4% and by 19,93% respectively, in the third experimental group decreased by 28.04%.Cortisol acquires different values in the groups after the experiment.In the first experimental group it decreases by 52.83%, in the second group it increases by 35.03% and in the third group it decreases by 27.5%.The immunological status of the experimental animals and immunoglobulin groups can be judged from the evaluation of blood proteins (Table 6).
Total protein in the experimental groups changes insignificantly and does not go beyond the normal physiological norm.Albumin levels are in the normal range.The level of globulins in experimental group 1 decreased by 9,93% after the treatment, while in the rest of the groups it corresponded to the average parameters.
Immunoglobulin A (Ig A) is responsible for the protection of mucous membranes of the respiratory organs of experimental animals.During the experiment we observed low levels of Ig A in sick calves before the experiment, in the group with triazavirin, in the control group, and only in calves with ingavirin does Ig A appear 0,88 g/l in the blood serum.
Immunoglobulin M (Ig M) is produced very early and provides an immune response to the introduction of the pathogenic agent.In the first experimental group, we observed a 1.39% decrease in the level of Ig M, in the second group a 31.7%increase, and in the third group a 66.7% increase.T-helper lymphocytes do not participate in the synthesis of Ig M, and their half-life period is 5 days.
Immunoglobulin G (Ig G) is involved in the long-term protection of the body against agents of viral and bacterial nature.There was an active increase of 20% in the first experimental group.In the second and third groups there was a decrease of 72.5% and 65.5% in Ig M, respectively.

Discussion
There is no mortality in experiment and treatment of calves with symptoms of respiratory system damage, in particular bronchopneumonia.In the first experimental group, when receiving inhavirin, the clinical condition of calves stabilizes on the eighth day; in the second experimental group, when receiving triazavirin, the condition stabilizes on the fifth day.
Analysis of average daily gains of animals in experimental groups showed that in the second group when triazavirin was administered, by the age of 6 months the gains were 171.97%, which exceeded the figures of the first group by 28,68% and the control group by 76.67%.
Analysis of haematological parameters shows a classical picture in sick animals: the presence of leukocytosis and lymphocytosis.When carrying out complex treatment, on the eighth day, in the first and second experimental groups, normalisation of the level of leucocytes and blood lymphocytes was noted.Such a pattern and changes are not specific to the respiratory disease group and the corresponding treatment given [8].
Biochemical blood parameters in sick calves before treatment deviate from the physiological norm.Alkaline phosphorus, GGTP, SIBC, de Ritis coefficient are significantly increased in all groups.In the first experimental group, the above parameters do not change significantly.In the second experimental group SIBC decreases to average physiological parameters.In the third experimental group the situation worsens, the urea level increases by 241.16%,AST by 126.69% and LDH by 116.1%, SIBC decreases by 22.5%.These changes indicate an infection load on the body, in particular on the cardiovascular system, on the metabolism, and can also result from intoxication and concomitant abnormalities (8).
Serum hormone levels change with animal treatment.In the second experimental group, with triazavirin we noted a slight increase in TSH (by 28.2%), as well as a moderate increase in T4 (by 21.7%), and an active reserve increase in T3 (by 19.93%).These figures indicate normalization of the hypothalamic-pituitary system and stabilization of the thyroid gland.
In the first experimental group, when receiving inhavirin, there was a sharp increase in TH (by 123.1%) and T4 (by 30.3%), against the background of a depletion of the T3 reserve (reduction by 4.45%).Such fluctuations will further lead to a sharp decrease in T4 and T3 levels.These figures indicate a stressful state of the hypothalamic-pituitary system and depressed thyroid hormonal function.
In the third experimental group, we observe the strongest destabilization of the hypothalamic-pituitary system.The increase in TH level is 1707.7%.T4 increases by 21.7%, which is an emergency compensatory mechanism in the thyroid gland, and its suppression is evidenced by T3 levels, which decrease sharply by 28.04% and are used for active T4 synthesis [7].
Total protein, albumin, globulins in the experimental groups correspond to the physiological norm.Immunoglobulins A, M, G provide protection against infectious agents and reflect the immune state of the body.
IgA consists of serum and secretory forms.A decrease in IgA concentration indicates insufficient humoral and local immunity, impaired synthesis or increased catabolism of IgA, as well as its adsorption to immune complexes [1,2,4,6,9,10].
IgM are antibodies of the acute period of the immune response that are synthesised by plasma cells during the first contact with a specific pathological agent.IgM has 10 antigen binding sites at a time, which is especially important during the acute period of infection, when there is a need for rapid recognition and elimination of a large number of pathogens.The ability of IgM to activate complement, which ensures complement-dependent cytotoxicity, is the strongest of all immunoglobulins, meets this requirement.High concentrations of specific IgM are registered from day 6 to 7 after infection, the later level of IgM decreases markedly against an increase in IgG, i.e. a switch from IgM to IgG synthesis occurs.The diagnostic significance of high specific IgM levels lies in the possibility of establishing the fact of an acute infection with a specific pathogen as the primary infection [1,2,4,6,9,10].
IgG are late-phase antibodies of the immune response that begin to be synthesised after a period of predominant IgM.IgG is a more specific antibody than IgM.High levels of specific IgG are registered during periods of clinical remission and recuperation in the acute inflammatory process.Specific IgG can be produced and circulate in the blood long after cure, as IgG is synthesized by immune memory cells.After an infection, either a stable concentration of specific IgG or a gradual decrease in IgG titres may occur.An increase in titers of specific IgG long after an acute illness indicates not the maintenance of immune memory, but incomplete cure and progression to a chronic form of infection, since IgG is an antibody of the secondary immune response, which is realized upon contact with a familiar antigen.Thus, in recurrent acute infection or acute exacerbation of chronic infection, the phase of IgM predominance is absent, as IgG is synthesized immediately [1,2,4,6,9,10].
In the experimental groups, IgA was not detected in sick calves when tested both before and after treatment, only when inhavirin was administered was an increase in IgA levels observed.IgA has a low concentration in small animals, and its concentration increases after the disease.Prolonged infection is characterized by a rapid rise in IgA and IgG antibody levels.IgA and IgG antibodies must be determined simultaneously for a complete picture of the condition.If the IgA result is unclear, confirmation of the disease is carried out with an additional IgM assay.
IgA appears in the blood of sick animals 10-14 days after virus entry.IgA antibody levels begin to decline 2-4 months after infection and disease, even after successful treatment.If reinfected, the IgA antibody level will rise again.After treatment, the IgA level should decrease, if it does not, it is an indication of a chronic infection.
In calves treated with triazavirin, there is an increase in IgM levels and a decrease in IgG levels.IgM antibodies are already detected in the blood 5 days after the onset of the disease and reach a maximum of 1 to 4 weeks, then decline to negligible levels over several months.An increase in IgM antibodies may indicate an acute form of the disease.
The function of IgG is to protect the body long term against bacteria, viruses.They form slowly, but they last for a long time, compared to IgM.IgG antibody levels rise slowly (15-20 days after the onset of the disease), but remain elevated longer than IgM, so they are a marker for long-term infection in the absence of IgM.Immunobulin G concentrations decrease with time, but rise rapidly with reintroduction of a similar antigen.
Conclusions. 1. Experimental use of the antiviral drug "Triazavirin" as part of complex therapy, to treat calves with symptoms of respiratory system lesions, bronchopneumonia, gave results, the animals recovered.No complications were observed during application of triazavirin and there was no mortality.2. Experimental application of the antiviral drug "Ingavirin" as a part of complex therapy, for treatment of calves with symptoms of respiratory system affection gave results, the animals recovered.Complications during application of Ingavirin were not observed and there was no mortality.3. Comparative analysis of application of antiviral preparations "Triazavirin" and "Ingavirin" in the complex therapy showed, that both antiviral preparations have therapeutic effect, but at application of Triazavirin clinical picture in case of disease improves earlier.Based on the results of the experiment, we recommend the use of the antiviral drug Triazavirin in the indicated doses to treat calves for infectious diseases of the respiratory system.

Conclusions
1.The experimental use of the antiviral drug "Triazavirin" as part of a complex therapy for the treatment of calves with symptoms of respiratory system damage gave good results, the animals recovered.Complications with the use of triazavirin were not observed, there is no lethality.2. The experimental use of the antiviral drug 'Ingavirin' as part of the complex therapy for the treatment of calves with symptoms of respiratory system damage gave good results, the animals recovered.Complications with the use of ingavirin were not observed, there is no lethality.3. A comparative analysis of the use of antiviral drugs "Triazavirin" and "Ingavirin" showed that both antiviral drugs have a therapeutic effect, but when using triazavirin, the clinical picture of the disease improves at an earlier time.According to the results of the experiment, we recommend using the antiviral drug Triazaverine in the indicated doses for the treatment of calves with infectious diseases of the respiratory system.

Table 2 .
Live weight and average daily gain of calves during the experiment

Table 3 .
Dynamics of haematological blood parameters for calves of experimental and control groups

Table 5 .
Concentration of hormones in blood serum of calves, Experimental and test groups