The Acute Toxicity Study Of Emulsified Isoflurane

Objective Oue previous studies carried out that 8% ( liquid volatile anesthetic volume percent) emulsified isoflurane administered by intravenous injection have many advantages over inhalational isoflurane. In present study, we investigated the acute toxicity of emulsified isoflurane for intravenous injection in rats and Beagles. This pilot study attempts to discover the toxic dose and toxic reaction for single intravenous injection of emulsified isoflurane, which applied reference for chronic toxicity study. What's more, we tried to find the dose-effect correlation and reversibility of toxic response so as to evaluate grossly the safety of this formulation and provide some clues for further researches.Methods In part â…  , we introduced the basal principle and some common methods for the acute toxicity study of new drug product. Further more, we list the mean objectives of the study. In part â…¡, we determined the toxic dose and acute toxicity action using the classic method for acute toxicity study- the Lethal Dose 50 method. 60 Sprgue-Dawley rats were randomly divided into LD₅₀ group (n=50) and control group (n=10). LD₅₀ group was further divided into 5 subgroups with 10 animals in each subgroup ( 5 male, 5 female ). The rat in LD₅₀ group received a single bolus of 1.88, 1.60, 1.36, 1.16, 0.99 ml·kg^-1 isoflurane injection via tail vein within 10 seconds respectively, and LD50 was calculated. In control group a single bolus of 30% lipid emulsion3 ml·kg^-1 was administered via tail vein within 10 seconds. The survived rats kept being observed for two weeks and were executed in the end of observation period.Autopsy and histopathological examination were carried for all dead rats. In part III, we investigate the acute toxicity of isoflurane injection in Beagles by a single dose intravenous (iv) injection and determine its approximate lethal dose (ALD) and maximal tolerance dose (MTD). Six Beagles aged 6⁸ months weighing 6⁸ kg were given a single bolus injection of isoflurane injection from 1.2 to 4.0 ml-kg"1 within 60 seconds. The equal gradient of two neighbouring dose was 0.3 ml-kg'1. No dog was subjected to more than one injection. The injection dose of latter dog depended on the last dog' s dose and toxic reaction. The survived dogs kept being observed for two weeks and were executed in the end of observation period. Autopsy and histopathological examination were carried for all dead Beagles. Seventy-five SD rats were randomly and equally assigned to three groups: ED50 group, control LD50 group and administered assistant ventilation LD50 group. ED50 and two LD5Os of IV isoflurane injection in rats were measured by Dixon' s up-and-down method. The loss of forepaw righting reflex (FRR) was accepted as successful induction of anesthesia. The therapeutic index (LD50/ ED50) was compared across administered assistant ventilation and control group. In part V, we discussed the result of above test and results. Meanwhile, we evaluated the anesthetic potency, safety and appliance outlook of emulsified isoflurane.Results Study of part II shows: The LD50 of isoflurane injection in rats via intravenous injection was 1. 423 ml-kg"1 which was equivalent 170.76 mg-kg"1, and 95% confidence limit (CL) was C 1.275 —1.588) ml-kg"1. Autopsy and histopathological examination did not show abnormality. Part III carried out that the ALD and MTD of isoflurane injection in Beagles via intravenous injection were 2.1 ml-kg"1 and 1.8 ml-kg'1, which were equivalent to 252 mg-kg"1 and 216 mg-kg"1 of liquid isoflurane respectively. Autopsy and histopathological examination did not show any abnormality. In part IV, ED50, control LD50 and administered assistant ventilation LD50 of IV isoflurane injection in rats were (0.70±0.14) ml-kg"1, (2.05±0.21) ml-kg'1 and (2.45±0.47) ml-kg"1 respectively. The therapeutic index (3.49) after administered assistant ventilation was longer than that (2.93) of control ventilation, but did not deffer significantly (P>0.05).Conclusion <ï¿¡> Reversible depression of cardiopulmonary is imputed to the acutetoxicity of isoflurane injection. (2) The toxic responses were correlated significantly with injection dose. The more the amount of dosage, the earlier and more serious the toxic responses appeared. (D Autopsy and histopathological examination did not show abnormality. (D Merely assistant ventilation can't expand the safety margin of IV isoflurane injection. (5) There is no significant stirps diversity of isoflurane injection' s toxic responses via intravenous injection.