| BackgroundBismuth drugs such as colloidal bismuth subcitrate are widely used in the treatment of the gastric and duodenal ulcer and anti-Hp (Helicobacter pylori)regimen. Bismuth-containing quadruple therapy is recommended as the first line eradication regimen in the high resistance region of clarithromycin in Maastricht-IV consensus. Anti-Hp treatment lasts for 2 weeks, however the bismuth agents are incorrectly used as gastric mucosal protective agents in some basic medical institutions because of the low price. As a non prescription agent, bismuth is often used repeatedly and lasts for too long, increasing the risk of renal failure and nervous system poisoning. Experiments show that the concentration of bismuth is very low if we take normal dose and regular course of agent. The possibility of having side-effect is very low. High-dose and long-term application of bismuth may cause extrapyramidal injury and renal failure. Patients with long-term and repeated use of bismuth, should pay attention to the potential risks caused by the accumulation of bismuth. And in every version of the clinical Pharmacopoeia of china are clearly claimed:acid-inhibitory drugs combine with bismuth can increase the accumulation of bismuth in the blood and can not take at the same time. Therefore,we designed a randomized controlled animal studies.Objective1?To observe the concentrations of bismuth in the serum, kidney,liver and encephalon of rats after administrating bismuth for 14,28 days repeatly.We also observe the changes of the relevant transaminase and each viscera pathology.2?To observe whether acid-inhibitory therapy has influences on the absorption of bismuth from CBS.MethodsExperiment 1) 70 male Wistar rats were divided into 5 groups randomly. Their weight varied from 230g to 250g. There were 14 rats in each group, which were administrated at dose levels of Omg/kg,40mg/kg(The human equivalent), 200mg/kg(Low-dose group,5 times),500mg/kg(Moderate-dose group,12.5 times) and 1000mg/kg(High-dose group,25 times) bismuth daily, lasting for 28 days. The serum bismuth concentrations of 4 rats in each group were observed at 14 days.4 rats in each group were put to death, the serum bismuth concentrations and the accumulation of bismuth in the kindey and brain of rats were detected at 28 days and 42 days.Experiment 2) 10 male Wistar rats ranging from 230g to 250g were randomly divided into 2 groups.5 rats were fed for 14 days at dose levels of 40mg/kg bismuth, and other 5 rats were given 40mg/kg bismuth and 3.6mg/kg Esomeprazole Magnesium Enteric-coated Tablets for 14 days. The serum bismuth concentrations of all the rats in each group were observed at 14 days.Results1?Results of experiment one:1.1 The serum bismuth concentrations:At 2 weeks, there were no significant differences between 200mg/kg group and 40mg/kg group (P>0.05). Differences were significantly among 200mg/kg group,500mg/kg group and 1000mg/kg group (P<0.05). At 4 weeks, there were no significant differences between 40mg/kg group,200mg/kg group,500mg/kg group and 1000mg/kg group (P>0.05). After drug withdrawal for 2 weeks, the blood bismuth concentration of each group decreased rapidly. There were no significant differences between 40mg/kg group and 200mg/kg group (P>0.05), but differences were significantly among 200mg/kg group,500mg/kg group and 1000mg/kg group (P<0.05). Data were shown in Table 1?2.1.2 The bismuth concentrations in the kidney,liver and encephalon:At 4 weeks, differences were significantly among 40mg/kg group,200mg/kg group and 500mg/kg group (P<0.05), but there were no significant differences between 500mg/kg group and 1000mg/kg group in the kidney and liver. After drug withdrawal for 2 weeks, the blood bismuth concentration of each group decreased rapidly. There were no significant differences between 200mg/kg group,500mg/kg group and 1000mg/kg group in kidney and liver (P>0.05). Differences in the encephalon were significantly among 200mg/kg group,500mg/kg group and 1000mg/kg group (P<0.05), but they were higher than 40mg/kg of bismuth concentration. Data were shown in Table 3-8.1.3 ?— GT)At 2 weeks, there were no significant differences between 40mg/kg group and Omg/kg group (P>0.05). Differences were significantly among 40mg/kg group,200mg/kg group and 500mg/kg group(P<0.05).There were no significant differences between 500mg/kg group and 1000mg/kg group (P>0.05). At 4 weeks, there were significant differences in 40mg/kg group and 200mg/kg group compared with 2 weeks. None difference between 500mg/kg group and 1000mg/kg group (P>0.05) compared with 2 weeks. After drug withdrawal for 2 weeks, the ?— GT concentration of each group decreased rapidly. There were no significant differences in 40mg/kg group,200mg/kg group,500mg/kg group and 1000mg/kg group compared with Omg/kg group (P>0.05). Data were shown in Table9.ALP)At 2 and 4 weeks,there were no significant differences between any group (P>0.05).ALT)40 mg/kg,200 mg/kg and 500 mg/kg each group and the blank group between two comparative differences had no statistical significance at2,4 and 6weeks.1000mg/kg group had significant differences between 2 and 4 weeks.There were significant differences in 1000mg/kg group at 4 weeks compared with 6 weeks,none between Omg/kg at 4 weeks.Data were shown in Table10.AST)At 2,4 and 6 weeks, there were no significant differences in 40mg/kg group, 200mg/kg group and Omg/kg group. There were significant differences in 500mg/kg group and 1000mg/kg group compared with Omg/kg group at 2 and 4 weeks,none between 500mg/kg and 1000mg/kg.There were no significant differences in 500mg/kg group and 1000mg/kg group at 4 weeks compared with 2 weeks.500mg/kg and 1000mg/kg group had significant differences at 6 weeks compared with 2 and 4 weeks,none between 500mg/kg group, 1000mg/kg group and Omg/kg group.Data were shown in Table10.1.4 The pathologic changes of the kidney, brain, encephalon tissue)At 4 weeks, only liver tissue of 1000 mg/kg group had degenerative changes.Kidney tissue of 1000mg/kg group had bleeding changes at 4 weeks.There was no obvious pathological change in brain tissue at 4 weeks.Each viscera more dose group were not seen significant pathological lesions.2?Results of experiment two:Compared with the 40mg/kg bismuth group, the serum bismuth concentrations were elevated in bismuth+PPI group (P<0.01)Conclusion1. Serum concentrations of bismuth increased along with the increase of dose of bismuth. At 4 weeks, serum concentrations of bismuth reached peak concentration.Discontinuation after 2 weeks serum bismuth concentration reduced quickly, within a certain dosage can drop to normal levels, more than the dose to normal level takes longer time.2.Bismuth element absorption into the bloodstream after deposition in the liver, kidney, encephalon, and volume as to increase with the increase of the dose and time, peaked at 4 weeks.Bismuth agent after reaching a certain drug concentration will cause ?—GT numerical changes, and in the certain concentration range increases with the increase of the dosage, beyond a certain numerical drug concentration dose not continue to rise.Bismuth concentration range ?—GT numerical value with the increase of the duration increases, beyond a certain numerical the duration of drug concentration was no longer positively proportional relationship.Serum ?—GT value in experimental bismuth agent concentration within the scope of withdrawal can be basic returned to normal after 2 weeks. Within the scope of experiment with bismuth agent concentration and time does not cause numerical changes of rat ALP.Rats in the dose of 1000 mg/kg bismuth agent ALT increased after 4 weeks, two weeks after discontinuation of serum ALT dropped to normal level.Rats taking 500 mg/kg and 1000 mg/kg bismuth agent after 2 weeks AST heighten, but did not present positive correlation with metering and time,2 weeks after discontinuation of 500 mg/kg and 1000 mg/kg group serum AST dropped to normal level.3. Bismuth accumulation can make pathology damage in liver and kidney tissue.4. Acid-inhibitory therapy caused an increase of absorption from CBS.PPI combined with bismuth had a higher risk of accumulation of serum bismuth than using high doses bismuth individually for a long term. |
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