The dissertation is devoted to the actual issue of experimental pharmacology - research and study of substances with anti-inflammatory and analgesic effects, promising for the creation of a new NSAID competitively with diclofenac.
The presence of anti-inflammatory effect in natrium (3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]hinazolin-6-il) alkylcarboxylate (NTHAC) and their halogen-containing analogues are predicted using the molecular docking methodwhich was subsequently confirmed by models of carragenin and zymosanovyedema of the hind limbs of rats. For the most effective NTHAC and the reference-drug diclofenac calculated the index ED50 antiphlogistic activity, according the size of which the connection leader DSK-38 twice the drug comparison (ED50 was 4,0 and 8,0mg/kg, i/hrespectively). The degree of anti-exudative effect of the NTHAC was due to the presence in the structure [1,2,4]triazino[2,3-c]hinazolin cycle, is determined by the length of the carboxylase fragment at position 6 and substantially depends on the substitute in position 3, as well as the presence of a fluorine in the molecule at position 9.
Analgesic activity is also characteristic of the NTHACand its halogen-containing analogues, which was most pronounced in the DSK-38 compound on models of nociceptive reactions induced in rats by electrical, thermal and chemical factors. Under the influence of the thermal agent, the compound DSK-38 by the size of ED50 practically equaled with ketolorak (3,8 mg/kg, i/h), exceeding diclofenac (6,6 mg/kg, i/h) and especially analgin (252 mg/kg, i/h).
The compound DSK-38 refers to non-narcotic analgesics, because, unlike tramadol, its combination with naloxone does not cause a decrease in the amount of analgesic effect. DSK-38 by the magnitude of acute toxicity of LD50 for mice and rats (correspondingly, 2240.0 and 2820.0mg/kg, i/h) refers to practically non-toxic substances classified by K.K. Sidorov (1973).
The therapeutic effect of DSK-38, as well as diclofenac, was clearly manifested in the model of adjuvant arthritis in rats, as indicated by the positive dynamics of clinical [reduction of the degree of inflammatory (correspondingly, 58and 53%) and nociceptive effects (correspondingly, 54 and 48%) in the affected joint], hematologic (ESR, number of leukocytes) and biochemical (MDA, SOD, seromucoid, gamma-glutamyl peptidase). In these conditions, the DSK-38 was not inferior to the efficacy, and sometimes exceeded diclofenac safely with respect to the gastrointestinal tract.
Caused by DSK-38 and diclofenac, positive changes in the marked rates of adjuvant arthritis in rats correlated with positive dynamics of the morphological picture of joint damage. In this case, the ability to weaken the signs of destructive and degenerative processes in the joint and periarticular tissues, DSK-38 to some extent predominated reference drag. Unlike diclofenac, on the background of DSK-38 there were no signs of histotoxicity in the liver, kidneys and adrenal glands, and ulcerogenicityto the gastrointestinal tract. On the model of experimental toxic stomatitis in rats, course medical effect of DSK-38 (2-minute application with 4% solution) was shown by a decrease of 26,7% (p<0,05) the average weight of the tongue of the animal relative to the control.
DSK-38 (4 mg/kg, i/h)unlike diclofenac (8mg/kg, i/h) does not inhibit the activity of PGH - synthase in the mucous membrane of the stomach of hungry rats, while restoring the activity of NO - synthase, which correlates with an increase in the level of stable metabolites of NO in the blood.
In the mechanism of anti-inflammatory effect DSK-38, as well as quercetin, antileukotrien action prevails.
Key words: (3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]hinazolin-6-il)alkylcarbonic acid derivatives, diclofenac, ketorolac, analgin, anti-inflammatory and analgesic effects, adjuvant arthritis, experimental stomatitis.
