Systemic Toxicity Of D-(+)-rabeprazole Sodium Injection Following Single-or Multiple-dose Administration

Proton pump inhibitors（PPIs）is currently one of the first-grade therapeutic drugs for peptic ulcers by inhibiting the secrete of gastric acid and the growth of helicobacter pylori（Hp）.PPIs,benzimidazole derivatives,inhibits the activity of H⁺/K⁺ -ATPase irreversibly to block intracellular H⁺/K⁺ exchange which results in the decrease of gastric acid secretion.Compared with H₂ receptor antagonists,PPIs have some advantages,including rapid onset,strong acid suppression,long duration,and convenient use,etc.Rabeprazole,was developed in Japan and came into the market in December,1998,and FDA approval for sale in The United States in August,1999.Compared with former PPIs,rabeprazole has the characteristics of little side effect,good curative effect.In recent years,researches showed that D-（+）-rabeprazole was the main pharmacological active form of rabeprazole.Therefore,we hope that D-（+）-rabeprazole can be developed to peptic ulcer drugs with good market prospect.The aim of this study was to investigate the toxic effect of D-（+）-rabeprazole sodium injection following single-or multiple administration and compared with racemic rabeprazole sodium injection.It will provide basis for the further clinical trials.1,Toxicityies of D-（+）-rabeprazole sodium injection in SD rats by single-doseThe acute toxicity of D-（+）-rabeprazole sodium injection by single intravenous administration in SD rats was observed by Bliss method.The LD₅₀ was calculated and other related toxicities were observe.After the intravenous injection of a single dose of D-（+）-rabeprazole sodium,SD rats immediately showed shortness of breath,prone motionless,convulsions,jumping,unsteady gait,urination defecation,righting reaction disappearance,exophthalmos and other symptoms.Symptoms was gradually alleviated and mortality was decreased with the reduction of dosage.The survived animals in each group returned to normal after 16-40 minutes of administration.We continued to observe these survived animals till 14 days after adminstration and found that they were in good general manner,had no obvious abnormalities and normal growth of body weight.In rabeprazole sodium group,rats showed the similar symptoms to that of D-（+）-rabeprazole sodium group.There were no obvious morphological changes in major organs of both dead rats and survival rats observed by naked eyes.LD₅₀ value of D-（+）-rabeprazole sodium injection following single intravenous dosewas 125.387mg/kg and 95%reliability limit was 118.599～132.563mg/kg.LD₅₀ value of rabeprazole sodium injection following single intravenous dose was 128.061mg/kg and 95%reliability limit was 119.784～136.909mg/kg.Comparing LD₅₀ and LD95 of these two drugs respectively.Results showed that the acute toxicities of marketed rabeprazole sodium injection are basically the same2.Toxicities of D-（+）-rabeprazole sodium injection in rats by multiple-doseThe chronic toxicities of D-（+）-rabeprazole sodium injection in SD rats were observed following intravenous administration once a day for consecutive 13wk.At the end of experiments,the adverse reactions,including the nature,extent,dose-response and time-response relationship and the reversibility were determined.Results showed that the performance of nerve system in rats showed shortness of breath,uncoordinated movements,limb weakness,lying motionless,salivate,etc.transient symptoms.The animals returned to normal after 4-5 minutes of administration.With the reduction of doses,symptoms gradually alleviated.With the prolongation of the administration period,the symptoms were relieved and the time of returning to normal was gradually shortened.During the recovery period,the survival animals in each group were in good general condition and showed no obvious abnormality and the normal growth of body weight.The main toxic target systems and organs are blood system,kidney,and thyrold,BUN contents in blood were decreased,kidney and stomach relative weight index was increased,thymus relative brain index was decreased.Pathological examination showed 80,20mg/kg/d doses respectively 60%and 20%of animal thyroid abnormalities.All the above mentioned symptoms recovered to normal completely after withdrawal.The comprehensive analysis showed that non-toxicity dose of D-（+）-rabeprazole sodium injection in rats by repeated administration was 5mg/kg/d,and about 17 times of the maximum daily clinical dose.In the same dose,the toxicity effects of D-（+）-rabeprazole sodium injection were the same as marketed rabeprazole sodium injection.