Siklosporinin kardiyovasküler risk faktörlerine olan etkisinin tavşanlarda araştırılması

Abstract

Cardiovascular mortality and morbidity is the major cause of death in the United ates, other industrialized countries and also in Turkey. When we look at the transplant cipients which is a minor group of the population, cardiovascular complications is the major luse of death in many industrialized countries. In Turkey it is the second most common tuse of death. The economic burden of cardiovascular disease to the society is enormous. In e transplant recipients, the cardiovascular complications cause person's death, graft lost and e lost of the money and time used for transplantation and graft survival. Today, prevention ems better than treatment and there is a great effort to reduce cardiovascular risk. For the population the major risk factors for atherosclerosis are dyslipidemia, ^pertension, tobacco use and diabetes mellitus. Other risk factors include physical inactivity, jesity, family history of coronary heart disease, gender, alcohol consumption and sycho logical factors. In transplant recipients, besides from above mentioned risk factors,.obably there are many other risk factors for this group. The medications that these people ive to use for prevention of graft rejection may be one of the risk factor. Today, ^perhomocysteinemia is an established but newly recognized important cardiovascular risk ictor. Hyperhomocysteinemia is common in transplant recipients. Cyclosporine-A is a îlective immunosuppressive drug used in transplantation and in some immunological iseases. It is believed cyclosporine -A can cause cardiovascular risk for chronic users,.ccording to some textbooks cyclosporine's effect on lipid metabolism is undetermined but :cent research showed a lipid increasing effect. Also recently, some authors reported that yclosporine can cause hyperhomocysteinemia but others could not find such an effect. jiother fact is that, all these researches are clinically made among transplant recipients. We ecided to conduct an experimental research to determine cyclosporine's effect on lipid and omocysteine metabolism. Twenty New Zealand white male rabbits are selected as suitable experimental animals. )aily subcutaneous cyclosporine is administered 10 mg/kg for the first 10 days and 20 mg/kg arice weekly for the next 3 weeks. Rabbit plasma cyclosporine-A level was controlled on day 0 and 4th. week of the study. Eight parameters ( total cholesterol, LDL cholesterol, HDL holesteroL triglyceride, lipoprotein-a, homocysteine, BUN, creatinin ) were studied on the eginning, at the 10th. day and 4th. week of cyclosporine treatment, and end of the 8th week. Tie blood is taken from the ear veins of the rabbits. The research is planned to be in twoıges. In the first 4 weeks cyclosporine's effect on homocysteine and lipid levels is amined, in the second 4 weeks the effect after cyclosporine withdrawal is observed. As we compare the results, the most statistically significant change ( p<0,001 ) curred in LDL cholesterol levels. The mean LDL level was 9,75+9.2 mg/dl in the ginning, raised to 24,9+17.6 mg/dl and 22,57±11.6 mg/dl on the 10th day and 4th week of ; study and reduced to a near normal range ( mean 12,10+10.8 mg/dl ) at the 8th week. The jst important change occurred in the first 4 weeks ( p<0,01). The increased LDL cholesterol /e/ continued during the cyclosporine administration period (when the plasma drug level is high) and, when cyclosporine stopped LDL cholesterol returned to a normal range. It 3ms cyclosporine has a LDL increasing effect. The mean total cholesterol level also ;reased significantly. For the first 4 weeks the increase was more significant (p<0,02). The îan total cholesterol level raised in the first 4 weeks and reduced later. In the beginning the 3an total cholesterol was 47.4+18 mg/dl then as cyclosporine-A was administered it raised 61.8±22.9 mg/dl on the 10th day and 60.3+17.6 mg/dl at 4th week. After cyclosporine ithdrawal mean total cholesterol returned to 51.5±26.2 mg/dl at the 801 week. We could not id any significant change in mean homocysteine levels (p>0.05). For HDL cholesterol there js also no significant change (p>0,05). For lipoprotein-a there was a significant increase at b 8th week (p<0,05). However, mean lipoprotein-a level did not show significant change ereafter. We observed a significant increase in the mean triglyceride level during closporin administration period ( p<0,001). At the beginning the mean triglyceride was )3.3±35.3 mg/dl, increased to 114.7+36.9 mg/dl on day 10 and 131.3+57.3 mg/dl at the 4th eek and decreased to 79.3±23.1 mg/dl at the 8th week. The mean value at the 8th week was wer than the beginning. In the last two weeks of the study period, we determined a fall in od consumption of rabbits. This can be a factor for the mean triglyceride level to be lower an the beginning. There was no significant change in the mean BUN levels ( p>0,05). Mean eatinine values significantly increased (p<0,01). However, the highest mean creatinine level as 1,035+0.2 mg/dl and all serum creatinine values were within the normal limits ( 0,8-2,7 g/dl). These results show us that cyclosporine-A has a tendency to increase total and LDL ıolesterol and triglyceride levels causing mixt hyperlipidemia. Probably cyclosporine has no îect on homocysteine metabolism. As a result, our findings suggest that cyclosporine-A seems to increase cardiovascular sk for the users. This probably occurs as hyperlipidemia ensues. Lipid values ( especially1 and LDL cholesterol ) must be periodically controlled for the people using cyclosporine- Higher values must be treated. In the treatment, cyclosporine-A can be reduced, a change n cyclosporine-A to tacrolimus can be managed and statins can be used. Still the best way v to treat these patients have to be determined. Statins can cause an additive toxicity in ients receiving cyclosporin-A. In ALERT study which is still running, transplant recipients treated with statins in association with cyclosporine use and this study is hoped to show r reduce in cardiovascular mortality and morbidity.