EXPERIMENTAL STUDY OF THE MEDIATOR MECHANISMS OF THE ANTINOCYCEPTIVE ACTION OF 4-[4-OXO-(4H)-QUINAZOLIN-3-YL]-BENZOIC ACID

Authors

  • H. I. Kramar NATIONAL PIROGOV MEMORIAL MEDICAL UNIVERSITY, VINNYTSYA
  • H. I. Stepaniuk NATIONAL PIROGOV MEMORIAL MEDICAL UNIVERSITY, VINNYTSYA
  • N. I. Voloshchuk NATIONAL PIROGOV MEMORIAL MEDICAL UNIVERSITY, VINNYTSYA
  • O. I. Alchuk NATIONAL PIROGOV MEMORIAL MEDICAL UNIVERSITY, VINNYTSYA

DOI:

https://doi.org/10.11603/mcch.2410-681X.2019.v.i4.10841

Keywords:

4- [4-oxo (4H) -quinazolin-3-yl] benzoic acid, nociception, mediator mechanisms, bradykinin

Abstract

Introduction. Previous studies have found that among derivatives of 4-oxo (amino) quinazoline, a leading substance, with pronounced analgesic action on different models of pain perception is 4- [4-oxo-4h-quinazolin-3-yl] benzoic acid (PK-66 compound).

The aim of the study – in-depth study of the main mechanisms involved in the implementation of analgesic action of a new original quinazoline derivative – PK-66 compounds.

Research Methods. Evaluation of the antinociceptive action of PK-66 (1 mg/kg i/h) was studied in rats, modeled on hyperalgesia, caused by the introduction of 0.1 ml of 1 % solution of carrageenin, 2 % suspension of zymosan and 0.01 % solution of bradykinin, which was injected subplantarly in left hind limb of an animal. The degree of nociception was determined using a dollarimeter by estimating the pain threshold. Diclofenac sodium (4 mg/kg) and corvitin (5 mg/kg) were used as reference drugs. The analgesic activity of the test compounds was evaluated by their ability to increase the pain threshold in the study groups compared to the control group and was expressed as a percentage. The anti-exudative activity of the compound and the reference preparations was determined by measuring the volume of paw edema using a plethysmometer. The degree of reduction of swelling in the experimental animals compared to the control group animals and was expressed as a percentage.

Results and Discussion. Compound PK-66 has the ability to eliminate hyperalgesia caused by various algogens. Its most pronounced analgesic effect was manifested against the introduction of bradykinin (53.4 %), less pronounced antinociception was found in carrageenan edema (38.5 %), and the least pronounced effect was on the model of zymosan hyperalgesia (26.9 %). The anti-exudative effect study showed that the degree of antiflogogenic action of PC-66 was more pronounced in the carrageenan swelling model (16.1 %) than zymosan (12.8 %). However, this effect did not reach statistically significant values for either carrageenan or zymosan edema, and in both cases was significantly inferior to the comparison drugs – diclofenac sodium compound (58.3 %) and corvitin (52.3 %).

Conclusion. The anti-mediating effect of PK-66 is more due to antagonism to bradykinin, to a lesser extent to prostaglandins and leukotrienes.

References

Bykov, Yu.N., Levina, G.Yu., & Alekseev, S.B. (2015). Diagnostika i lechenie neyropaticheskoy boli pri zabolevaniyakh perifericheskoy nervnoy sistemy [Diag­nosis and treatment of neuropathic pain in diseases of the peripheral nervous system]. Sibirskiy meditsinskiy zhurnal – Siberian Medical Journal, 3, 28-30 [in Russian].

Zozulia, I.S., Maksymenko, M.V., & Zozulia, A.I. (2016). Bil: pidkhody do diahnostyky ta likuvannia v nevrolohii ta khirurhii [Pain: approaches to diagnosis and treatment in neurology and surgery]. Ukr. medychnyi chasopys – Ukrainian Medical Journal, 2 (112), 37-39 [in Ukrainian].

Korzh, A.N. (2017). Ostryy bolevoy sindrom v praktike semeynogo vracha [Acute pain in the practice of a family doctor]. Retrieved from: http://www.mif-ua.com/archive/article/44421#prettyPhoto.

Clarke, T.C., Nahin, R.L., Barnes, P.M., & Stus­s­man, B.J. (2016). Use of complementary health approaches for musculoskeletal pain disorders among adults: United States, 2012. Natl. Health Stat. Report., 98, 1-12.

Mamchur, V.Y., & Khomiak, O.V. (2011). Depresiia ta bil: deiaki pytannia komorbidnosti ta likuvannia (ohliad) [Depression and pain: Some issues of comorbidity and treatment (review)]. Morfolohiia – Morphology, 3, 24-34 [in Ukrainian].

Torrance, N., Elliott, A., Lee, A., & Smith, B. (2010). Severe chronic pain is associated with increased 10 year mortality. A cohort record link-age study. European Journal of Pain, 14, 380-386.

Morgan, B., & Wooden, S. (2018). Diagnosis and treatment of common pain syndromes and disorders. Nurs. Clin. North. Am., 53, 3, 349-360. DOI: 10.1016/j.cnur.2018.04.004.

Khodakivskyi, O.A. (2009). Neiroprotektorna diia pokhidnykh 4-okso(amino-) khinazolinu pry ekspery­mentalnii ishemii holovnoho mozku [Neuroprotective effect of derivatives of 4-oxo (amino) quinazoline in experimental cerebral ischemia]. Extended abstract of Candidate’s thesis. Оdesa: Odesa State Medical Uni­versity [in Ukrainian].

Alchuk, O.I. (2011). Aktoprotektorni vlastyvosti novykh pokhidnykh 4-okso(amino-)khinazolinu (eksperymentalne doslidzhennia) [Actoprotective properties of new 4-oxo (amino-) quinazoline derivatives (experimental study)]. Extended abstract of Candidate’s thesis. Kyiv: Institute of Pharmacology and Toxicology, of AMS of Ukraine [in Ukrainian].

Yurchenko, A.I. (2013). Skryninh analhetychnoi dii pokhidnykh 4-okso(amino-) khinazolinu [Screening of analgesic action of 4-oxo (amino) quinazoline derivatives]. Farmakol. ta likarska toksykolohiia – Pharmacological and Medicinal Toxicology, 2 (33), 89-91 [in Ukrainian].

Pavlov, S.V. (2007). Tserebroprotektyvna aktyvnist pokhidnykh (4-okso-4-N-khinazolin-3-il)-alkil (aryl) karbonovykh kyslot v umovakh imobilizatsiinoho stresu [Cerebroprotective activity of (4-oxo-4-H-quinazolin-3-yl)-alkyl (aryl) carboxylic acid derivatives under conditions of immobilization stress]. Extended abstract of Candidate’s thesis. Kyiv: Institute of Pharmacology and Toxicology of AMS of Ukraine [in Ukrainian].

Kramar, H.I. (2017). Experimental study of analgesic effect of new 3-(2-R1-6-R2-4-oxyquinoline-3(4H)-yl)alkyl (alkaryl, aryl) carboxylic acid derivative (PC-66 compound). Curierul Medical, 1, 32-34.

Kramar, H.I. (2017). Experimental study of state of gastric mucosa in rats under introduction of new derivate of 4-[4-oxo-4h-quinazoline-3-yl] benzoic acid (pc-66). ScienceRise: Pharmaceutical Science, 2 (6), 53-58.

Yurchenko, A.I., Stepaniuk, H.I., Alchuk, O.I., Kovalenko, S.I., & Shabelnyk, K.P. (2014). Porivnialna otsinka hastrotoksychnosti pokhidnykh 4-okso(amino-) khinazolinu (spoluk PK-66 ta PK-199), dyklofenaku ta ketorolaku pry yikh tryvalomu vvedenni v orhanizm [Comparative evaluation of the gastro-toxicity of 4-oxo (amino-) quinazoline derivatives (PK-66 and PK-199), diclofenac and ketorolac derivatives with prolonged administration]. Ukrainskyi biofarmatsevtychnyi zhurnal – Ukrainian Biopharmaceutical Journal, 6 (35), 60-63 [in Ukrainian].

Kramar, H., Stepaniuk, H.I., Voloshchuk, N.I., Taran, I.V., Alchuk, O.I., Kovalenko, S.I., & Schabelnyk, K.P. (2018). Experimental study of pain-relieving mechanisms of 4-[4-oxo-(4h)-quinazolin-3-yl]-benzoic acid (PK-66 compound). Georgian Medical News, 10 (283), 148-154.

Pavlenko, A.Yu., & Hizhniak, A.A. (2006). Bolevoy sindrom: patofiziologicheskie mekhanizmy razvitiya i metody vozdeystviya na etapakh okazaniya meditsinskoy pomoshchi [Pain syndrome: pathophysiological mechanisms of development and methods of exposure in the stages of care]. Meditsina neotlozhnykh sostoyaniy – Emergency Medicine, 1 (2), 16-19 [in Ukrainian].

Churyukanov, V.V. (2003). Neyrohimicheskiy analiz i farmakologicheskaya regulyatsiya kortikofugalnykh mekhanizmov kontrolya notsitseptivnyh signalov v afferentnykh putyakh [Neurochemical analysis and pharmacological regulation of corticofugal mechanisms for controlling nociceptive signals in afferent pathways]. Eksperim. i klinich. farmakologiya – Experimental and Clinical Pharmacology, 2, 24-31 [in Russian].

Poberezhnyy, V.Y., & Marchuk, A.V. (2016). K voprosam fenomena “bol”. Formulirovanie definitsii “bol” na osnove sistemnogo podkhoda [To the issues of the "pain" phenomenon. Formulation of the definition of “pain” based on a systematic approach]. Pain Medicine, 1, 6-21 [in Russian].

Kukushkin, M.L., & Hitrov, N.K. (2004). Obshchaya patologiya boli [General pathology of pain]. Moscow: Meditsina [in Russian].

Jetzer, A.K. (2009). Cross-modal plasticity in the human thalamus: evidence from intraoperative macro­stimulations. Neuroscience, 164, 1867-1875.

Trinus, F.P., Gandzha, I.M., Klebanov, B.M., & Seyfulla, R.D. (1987). Farmakologicheskaya regulyatsiya vospaleniya [Pharmacological regulation of inflammation]. Kyiv: Zdorovia [in Russian].

Yakovleva, L.V., Obolentseva, H.V., & Briuzhіno­va, L.P. (2011). Eksperymentalne vyvchennia novykh protyvyrazkovykh preparatіv. Doklіnіchnі doslіdzhennia lіkarskykh zasobіv: method. recomen. [Experimental study of new antiulcer drugs. Preclinical drug research: guidelines]. Stefanov, O.V. (Ed.). Kyiv: Avitsena [in Ukrainian].

Lang, T.A., & Sesik, M. (2011). Kak opisyvat statistiku v meditsine [How to describe statistics in medicine]. Annotated Guide for Authors, Editors, and Reviewers: trans. from English. Moscow: Prakticheskaya meditsina [in Russian].

Yurchenko, A.I., Stepaniuk, H.I., Alchuk, O.I., Kovalenko, S.I., & Shabelnyk, K.P. (2015). Porivnialna otsinka vplyvu 4-[4-okso-(4H)-khinazolin-3-il] benzoinoi kysloty (spoluka PK-66) ta dyklofenaku na perebih ad­iuvantnoho artrytu u shchuriv [Comparative evaluation of the effect of 4- [4-oxo- (4H) -quinazolin-3-yl] benzoic acid (PC-66 compound) and diclofenac on the course of adjuvant arthritis in rats]. Farmakol. ta likarska toksykolohiia – Pharmacological and Medicinal Toxicology, 4-5 (45), 103-107 [in Ukrainian].

Ricciotti, E., & FitzGerald, G.A. (2011). Prosta­glandins and inflammation. Arterioscler Thromb. Vasc. Biol., 31(5), 986-1000.

Brune, K., & Patrignani, P. (2015). New insights into the use of currently available non-steroidal anti-inflammatory drugs. J. Pain Res., 8, 105-18.

Published

2020-02-04

How to Cite

Kramar, H. I., Stepaniuk, H. I., Voloshchuk, N. I., & Alchuk, O. I. (2020). EXPERIMENTAL STUDY OF THE MEDIATOR MECHANISMS OF THE ANTINOCYCEPTIVE ACTION OF 4-[4-OXO-(4H)-QUINAZOLIN-3-YL]-BENZOIC ACID. Medical and Clinical Chemistry, (4), 67–73. https://doi.org/10.11603/mcch.2410-681X.2019.v.i4.10841

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Section

ORIGINAL INVESTIGATIONS