Therapeutic efficacy of N-cholinolitic drug N,N-diethyl-5,5-diphenyl-2-pentynylamine in models of non-cardiogenic pulmonary edema

The existing non-cardiogenic pulmonary edema (NCPE) treatment methods are not sufficiently effective. N,N-Diethyl-5,5-diphenyl-2-pentynylamine hydrochloride  (DDPA), the N-cholinolitic drug, is of interest as a potential remedy for treatment of toxic pulmonary edema (TPE). The study was aimed to determine therapeutic efficacy of the drug in animal TPE models. TPE in white rats was induced through intraperitoneal thiourea injection or nitrogen dioxide inhalation. Treatment of  animals involved inhalation of the DDPA aqueous solution. The efficacy was estimated based on the animals’ survival rate and lung gravimetry data. The results were assessed based on descriptive statistics using the Student's t-test. In the model of thiourea-induced NCPE, the drug administered after the toxic exposure increased the animals’ survival rate and significantly decreased lung hydration levels (149% vs. 262.5% in non-treated animals). In the model of nitrogen dioxide- induced NCPE, the drug significantly increased the rats’ survival rate within the period between 0 and 5 h, however, the differences became non-significant within 24 h. The treated animals had 15–20% lower respiratory rate and pulmonary coefficients than non-treated animals 5 h after the NO₂ exposure. The use of DDPA improved the survival rate and overall health in both TPE models, however, the thiourea-based model showed better treatment outcomes compared to the NO₂–based model. Such differences can be explained by the deeper and more disruptive nature of the lung tissue injury caused by nitrogen dioxide compared to that caused by thiourea. Thus, the use of DDPA in individuals with injuries induced by pulmonotoxic chemicals may be promising at the prehospital stage

1. Bernard GR, Artigas A, Brigham KL. The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. Amer J Resp Crit Care Med. 1994; 149 (3): 818–24.

2. Jarosheckij AI, Grican AI, Avdeev SN, Vlasenko AV, Eremenko AA, Zabolotskih IB, i dr. Diagnostika i intensivnaja terapija ostrogo respiratornogo distress-sindroma. Anesteziologija i reanimatologija. 2020; 2: 5–39. Russian.

3. Korovin AE, Novickij AA, Makarov DA. Ostryj respiratornyj distress- sindrom. Sovremennoe sostojanie problemy. Klinicheskaja patofiziologija. 2018; 24 (2): 32–41. Russian.

4. Pugach VA, Chepur SV, Tjunin MA, Vlasov TD, Stepanov AV, Nikishin AS, i dr. Molekuljarno-kletochnye osnovy patogeneza ostrogo respiratornogo distress-sindroma. Sovremennye podhody k patogeneticheskoj terapii. Patogenez. 2021; 19 (4): 4–14. Russian.

5. Torkunov PA, Shabanov PD. Toksicheskij otek legkih: patogenez, modelirovanie, metodologija izuchenija. Obzory po klinicheskoj farmakologi i lekarstvennoj terapii. 2008; 8 (2): 3–54. Russian.

6. Kucenko SA. Osnovy toksikologii. SPb.: Izdatel'stvo Foliant, 2004; 720 s. Russian.

7. Tolkach PG, Sizova DT, Basharin VA, Chepur SV, Vengerovich NG, Aleshina OI, Ivanov IM, Chajkina MA. Rol' akvaporina-5 v formirovanii oteka legkih razlichnogo geneza. Uspehi sovremennoj biologii. 2022; 142 (2): 193–8. Russian.

8. Kucenko SA, redaktor. Voennaja toksikologija, radiobiologija i medicinskaja zashhita. SPb.: Izdatel'stvo FOLIANT, 2004; 528 s. Russian.

9. Basharin VA, Chepur SV, Shhjogolev AV, Haritonov MA, Tolkach PG, Judin MA, i dr. Rol' i mesto respiratornoj podderzhki v shemah terapii ostrogo legochnogo oteka, vyzvannogo ingaljacionnymvozdejstviem toksichnyh veshhestv. Voen.-med. zhurn. 2019; 11: 26–32. Russian.

10. Mashkovskij MD. Lekarstvennye sredstva. M.: «Novaja Volna», 2006; 1206 s. Russian.

11. Vlasenko AV, Evdokimov EA, Rodionov EP. Sovremennye algoritmy respiratornoj podderzhki pri ORDS razlichnogo geneza (lekcija). Vestnik anesteziologii i reanimatologii. 2020. 17 (4): 41– 58. Russian.

12. Pugach VA, Chepur SV, Tjunin MA, Vlasov TD, Stepanov AV, Nikishin AS, i dr. Molekuljarno-kletochnye osnovy patogeneza ostrogo respiratornogo distress-sindroma. Sovremennye podhody k patogeneticheskoj terapii. Patogenez. 2021; 19 (4): 4–14 DOI: 10.25557/2310-0435.2021.04.4-14. Russian.

13. Vlasenko AV, Evdokimov EA, Rodionov EP. Sovremennye principy korrekcii gipoksii pri ORDS razlichnogo geneza. Chast' 1. Vestnik anesteziologii i reanimatologii. 2020; 17 (3): 61–78. Russian.

14. Sherbashov KA, Basharin VA, Marysheva VV, Konshakov JuO, Shabanov PD. Jeksperimental'naja ocenka jeffektivnosti antigipoksantov pri toksicheskom oteke legkih, vyzvannom oksidom azota (IV). Obzory po klinicheskoj farmakologii i lekarstvennoj terapii. 2016; 14 (2): 65–68. Russian.

15. Tolkach PG, Basharin VA, Chepur SV, Potapov PK, Sizova DT, Dimitriev JuV. Ocenka jeffektivnosti sedativnyh preparatov dlja korrekcii toksicheskogo oteka legkih u laboratornyh zhivotnyh pri intoksikacii produktami piroliza ftoroplasta-4. Uspehi sovremennoj biologii. 2021; 141 (1): 32–39. Russian.

16. Dubrovskij KA. Ocenka jeffektivnosti 5-ftoruracila i jemodina dlja korrekcii toksicheskogo oteka legkih u krys pri intoksikacii produktami piroliza ftoroplasta-4 / Izvestija Rossijskoj voenno- medicinskoj akademii. 2022; 41 (S2): 144–7. Russian.

17. Barinov VA, Bonitenko EYu, Beljakova NA, Rodchenkova PV, Tonshin AA, Panfilov AV, i dr. Ispol'zovanie perftoruglerodnyh zhidkostej v lechenii respiratornogo distress-sindroma. Rossijskij biomedicinskij zhurnal. 2022; 23 (1): 515–55. Russian.

18. Karkishhenko VN, Pomytkin IA, Gasanov MT, Stepanova OI, Kljosov RA, Ogneva NS, i dr. Sochetannoe primenenie lejtragina i legochnogo surfaktanta-BL povyshaet vyzhivaemost' zhivotnyh v modeli fatal'nogo ostrogo respiratornogo distress-sindroma. Biomedicina. 2020; 16 (4): 52–59. Russian.

19. Zemljanoj AV, Onikienko SB, Vivulanec EV, Varlashova MB, Torkunov PA, Borodavko VK. Zashhita ot respiratornogo distress- sindroma pri ingaljacionnom otravlenii pul'monotoksikantami. Rossijskij biomedicinskij zhurnal. 2020; 21: 613–9. Russian.

20. Tolkach PG, Basharin VA, Chepur SV. Jeksperimental'naja model' toksicheskogo otjoka legkih pri ingaljacii produktov piroliza hlorirovannogo parafina. Toksikologicheskij vestnik. 2018; 6: 8–11. Russian.

21. Kolbasov KS. Jeksperimental'noe obosnovanie kompleksnogo lekarstvennogo sredstva dlja ingaljacionnogo primenenija priporazhenijah, vyzvannyh pul'monotoksikantami [dissertacija]. SPb., 2016; 214 s. Russian.

22. Ivanov MB, Rozhko MA, Lapina NV, Melihova MV, Bespalov AYa. Krasnov KA, Vakunenkova OA, avtory. Zajavitel' FGBUN IT FMBA Rossii. Primenenie N,N-dijetil-5,5-difenil-2-pentinilamina gidrohlorida dlja lechenija nekardiogennogo oteka legkih: N 2020122970: zajavl. 06.07.2020. Patent N 2762495 Rossijskaja Federacija, MPK A61K 31/132 (2006.01) A61P 11/00 (2006.01). 21.12.2021. Russian.

23. Lopatko VS. Prediktory razvitija toksicheskogo oteka legkih u laboratornyh zhivotnyh pri intoksikacii veshhestvami pul'monotoksicheskogo dejstvija. Izvestija Rossijskoj voenno- medicinskoj akademii. 2020; 39 (1): 53–59. Russian.

24. Rukovodstvo po provedeniju doklinicheskih issledovanij lekarstvennyh sredstv. Chast' pervaja. M.: Grif i K, 2012; 235 s. Russian.

25. Prozorovskij VB. Statisticheskaja obrabotka rezul'tatov farmakologicheskih issledovanij. Psihofarmakol. biol. narkol. 2007; 7 (3–4): 2090–120. Russian.