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Proteolysis Inhibitor E-Aminocaproic Acid as Effective Drug for Prevention and Treatment of Influenza, Other Acute Respiratory Viral Infections and their Bacterial Complications
V. Lozitsky 1 , A. Fedchuk 1 , T. Grydina 2 , L. Shytikova 3 , L. Mudryk 3 , S. Socheslo 3 , M. Lebediuk 4 , O. Voronkov 5 , V. Trykhlib 6 , A. Frolov 7 , V. Zadorozhna 7 , V. Buiko 8 , S. Tkachuk 9

1  Research Center “Biomedical Testing of Preparations and Products”, Odessa, Ukraine,I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of Health, Odessa, Ukraine
2  I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of Health, Odessa, Ukraine,Odessa National Medical University, Odessa, Ukraine
3  I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of Health, Odessa, Ukraine
4  Research Center “Biomedical Testing of Preparations and Products”, Odessa, Ukraine,Odessa National Medical University, Odessa, Ukraine
5  State Enterprise “Research Enterprise Institute of Chemical Technology “Chemtechnology”, Sevtodonetsk, Ukraine
6  Ukrainian Military Medical Academy, Kyiv, Ukraine
7  L.V.Gromashevsky Institute of E pidemiology and Infectious Diseases of NAMS of Ukraine, Kyiv, Ukraine
8  Odessa National Medical University, Odessa, Ukraine
9  Military Medical Clinical Center of the Western Region, Lviv, Ukraine

Published: 09 November 2015 by MDPI AG in 1st International Electronic Conference on Medicinal Chemistry in 1st International Electronic Conference on Medicinal Chemistry
MDPI AG, 10.3390/ecmc-1-A050
Abstract:

The proteolytic cleavage is the universal mechanism of specific proteins activation. The activation of proteolysis plays an important role in the pathogenesis of many diseases including viral infections. The results of our research and the scientific data have made it possible to formulate the concept of formation of a “vicious circle”: virus activates the proteolytic systems, which in turn assists the development, generalization, and aggravation of the infectious process at the expense of influence on the etiological and pathogenetical factors. Inhibitors of proteolysis (IP) may prevent the formation or destroy this “vicious circle”. Usually IP E-aminocaproic acid (name of medicine “Aminocaproic acid” - ACA) is used for    hemostasis when fibrinolysis contributes to bleeding. ACA is a low toxic drug. The intravenous and oral LD50 of ACA are 3.0 and 12.0 g/kg respectively in mice. ACA prevents the enhancement of proteolysis during the interaction of virions with cell membranes and decreases penetration of virions into sensitive cells. It brings down proteolytic cleavage of HA precursor to HA-1 and HA-2 and reduces the infectious virus harvest. It has been shown that, in vitro, ACA exhibits high levels of anti-influenza efficacy on subtypes H1N1; H2N2; H3N2 of human, H5N3 and H7N3 avian influenza A viruses and on influenza B viruses. ACA promotes the intensification of specific antibodies production and cell immunity, prevents vessels permeability and hemorrhagic phenomena and decreases the destruction of bronchi epithelium. Mice treated by ACA after primary infection were more protected to re-infection. ACA decreased the virus reproduction in lungs and also enhanced  the humoral immune response when used  in the prevention and treatment of influenza. Farmaceutic Center and Ukrainian Ministry of Public Health, on the basis of our experimental research and clinical trials, have allowed using ACA as antiviral for prevention and treatment of influenza and other acute respiratory viral infections (ARVIs) in children and adults. The results of including ACA in the therapeutic complex for treatment of influenza and other ARVIs in children were: decrease of duration of intoxication symptoms on 2-3 days, of fever on 1.5-3 days, of catarrhal symptoms on 1.5-2 days. Number of complications was reduced to 17%. Prophylactic efficacy of ACA was also established. With the scope to study the ACA prophylactic activity in organized collectives, we have prescribed it per-orally in 2.0 g dose four times a day during a week. The monitoring was performed in two independent collectives (923 young adults males aged 18-19 years old) during acute respiratory diseases appraisal. As the reference, 4 groups were taken (2 from each collective) but without  ACA application. The obtained results show: compare to the high morbidity rates in the reference group of the first tested collective in the basic group preventively treated with ACA, number of ARVIs has decreased in two-fold. At the same time, compare to the morbidity rate growth of ARVIs (by 15-27%), quinsy (by 14-21%) and pneumonia (by 6-7%) in the reference groups of the second tested collective, of the main examined group treated with ACA, pneumonia morbidity rate has decreased up to five-fold, while the ARVIs and quinsy levels were stabilized. The smallest number of cases of these infections in both teams surveyed was recorded in the period of ACA application. The obtained results allow to recommend the use of ACA for the efficient prophylaxis of ARVIs, quinsy and pneumonia in the organized collectives in the period of increased incidences of these infections. It is known that use of agents with different mechanisms of antiviral actions may have as result synergistic effects. Our studies of anti-influenza activity in vitro and in vivo show that the results of combined action of ACA with Tamiflu are synergistic antiviral effects. We have studied the influence of ACA on the growth of S.aureus. Strains  АТСС 25923, 2781 and Kunda of Staphylococcus aureus were  used.  It was stated that ACA taken in final concentration of 15, 10 and 7.5%, has hindered the growth of S.aureusАТСС 25923 totally. It is known that the IP increases the sensitivity of some microorganisms to antibiotics. We have shown that  ACA inhibits the reproduction of various strains of S.aureus that have different sensitivity to antibiotics. ACA can strengthen the antimicrobial action of antibiotics against the studied strains of Staphylococcus aureus. So use of ACA for treatment of influenza and other ARVIs simultaneously prevents bacterial complications.

 Conclusion E-aminocaproic acid is an effective remedy for prevention and treatment of influenza  and  acute respiratory viral infections in children and adults and  simultaneously for prevention of bacterial complications. The combination of proteolytic inhibitor E-Aminocaproic acid with neuraminidase inhibitor Tamiflu constitutes a promising perspective in anti-influenza protection and therapy.


Comments on this paper Get comment updates
Valeriy Kublanovsky
doi:10.3390/ecmc-1-A050
The investigation of proteolysis inhibitor aminocaproic acid as effective drug for prevention and treatment of influenza it interest since. Therefore, research in the field of respiratory viral infections and their bacterial complications and the study of their consequence are practical interest.
I consider that combination of proteolytic inhibitor on the basis of aminocaproic acid with neuraminidase inhibitor Tamiflu constitutes and promising perspective in anti-influenza protection and therapy.
Professor V.Kublanovsky

John Drach
Comment on paper by Lozitsky et al.
I find the results of the study to use E-aminocaproic acid (ACA) to prevent and treat influenza to be very significant because this is a new use for an established drug that has known properties. Further, the observation that the use of agents with different mechanisms of antiviral action often result in synergistic effects is correct. The application of this principle to the authors’ study of the combined action of ACA with Tamiflu to give synergistic antiviral effects is noteworthy.
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David Mccrae
Lozitsky et al. paper
A very interesting paper with applications beyond what is presented.

Alexander Skurla
aminocaproic acid
My opinion is that it is useful to go on in research and usage of proteolysis inhibitor E-aminocaproic acid as a tool to treat viral infections. It could be useful and benefitial tool.

Joe Colacino
Lozitsky et al., E-aminocaproic acid for influenza virus infections
Dr. Lozitsky and this group present very important data regarding the repurposing of E-amino caproic acid for the preventative and therapeutic intervention of influenza virus infections. The work is timely and well done. Importantly, Lozitsky et al offer new possibilities to our armamentarium against influenza. This is an important consideration in the event of a pandemic infection. The work is commendable.


Elric Saaski
Aminocaproic Acid article
This article describes further work showing the efficacy of aminocaproic acid as a weapon in the battle against influenza virus. This very interesting approach has received little attention in the Western world, but perhaps viewed as a synergistic complement to other medications it can gain more widespread acceptance.


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