Isobolographic analysis of analgesic interactions of silymarin with ketamine in mice

Abstract

The present study was undertaken to explore the analgesic effect of silymarin and ketamine alone or in combination in mice. Analgesia was measured by using a hot plate and the writhing test. The up-and-down method was used to determine the median effective analgesic dosages (ED50s) of silymarin and ketamine administered intraperitoneally (ip) either alone or together. The ED50s of both drugs were analyzed isobolographically to determine the type of pharmacological interaction between them. The analgesic ED50s for silymarin and ketamine in mice were 57.22 and 1.96 mg/kg, ip, respectively. Concomitant administration of the silymarin and ketamine at fixed ration (0.5:0.5) of their individual ED50s was 38.4 mg/kg and 1.28 mg/kg, ip, respectively. Silymarin and ketamine at fixed ration (1:1) of their individual ED50s were 47.54 mg/kg and 1.58 mg/kg, ip, respectively . Depending on the isobolographic analysis and calculating Y value, the type of pharmacological interaction between silymarin and ketamine at a ratio of 0.5:0.5 and 1:1 of their analgesic ED50 values of each drug , was antagonistic .In the writhing test the concomitant administration of silymarin and ketamine at 120mg/kg and 4mg/kg , ip, respectively reduce significantly the numbers of writhing in compare with silymarin120 mg/kg,ip and ketamine 4mg/kg, ip separately. The results suggest that the co-administration of silymarin and ketamine was ineffective to reduce the central pain while the concomitant administration of silymarin and ketamine was effective to reduce the visceral pain.

The Safety Profile of the Anesthetic Effect of Alfaxalone and its Interaction with Xylazine and Ketamine in Chick’s Model (Gallus Gallus Domesticus)

“…The estimated ED 50 of alfaxalone, ketamine, and xylazine, as well as the ED 50 of alfaxalone/ketamine and alfaxalone/xylazine (25:25 of their individual anesthetic ED 50 values), were used for the isobolographic analysis which determined the level of drug interaction. The induction of anesthesia was confirmed by loss of righting reflex and consciousness within 30 minutes (15,18). The ED 50 value of alfaxalone was marked on the x-axis and those of ketamine and xylazine on the y-axis, connected by a straight diagonal line.…”

“…The chicks were monitored for anesthesia onset (losing the righting reflex and unconsciousness) within two hours. The doses of alfaxalone were decreased or increased by 10 mg depending on the anesthetic effect (14,15 d = increase or decrease in the dosage Ataxia, relaxation, closed eyelids, loss of righting reflex, and sleep within 1-2 minutes were considered as positive signs of anesthesia induced by alfaxalone (16).…”

“…The ED 50 value of alfaxalone was marked on the x-axis and those of ketamine and xylazine on the y-axis, connected by a straight diagonal line. The ED 50 values of the combined treatments on, above, or beneath the diagonal line were considered as an additive, antagonistic, or synergistic effect, respectively (12,19,20,21). The interaction index (Y) was estimated with the following equation da/Da+db/Db (20), where 'Da' and 'Db' represent the anesthetic ED 50 of alfaxalone, and ketamine or xylazine respectively, while da and db are the ED 50 of alfaxalone/ketamine or alfaxalone/xylazine.…”

Methods of Pain Assessment in Chicks as a Model

“…The jumping test first describes by Hughes [43]. This test is resemble to the hotplate test in the mice [44]. The apparatus of this test comprised of a 63 x 20 x 0.3 centimeter.…”

“…Left foot planter was injected 15 minutes before the injection of formalin with a physiological saline solution as a control test or with analgesic medicine. The latency to raise the correct foot, longest foot lift time, and Repetition to raise the injected foot in reaction to irritant (formalin) injection were recorded within 3 minutes immediately after the formalin injection [44].…”