Blunting cyclosporine's kidney toxicity.

Blunting cyclosporine's kidney toxicity

Hailed as a breakthrough in organ transplantation, the drug cyclosporine suppresses the immune system, reducing the chances of transplant rejection. More recently, scientists have been testing the drug as a treatment of uspected autoimmune diseases, such as type I diabetes (SN: 11/7/8, p.292). But cyclosporine is toxic to the kidneys and frequently causes high blood pressure. Now, William M. Bennett of Oregon Health Sciences University in Portland Reports on his research and that of other aimed at minimizing the drug's toxicity.

At the front line of this effort, says Bennett, is the development of more sensitive techniques for monitoring levels of the drug. The most promising of these, he says, are monoclonal antibodies that affix to the drug in the patient's blood. But even when such a test is available, researchers will continue to walk the narrow line between cyclosporine doses that are effective and those that are toxic. According to Bennett, those doses are likely the same--suggesting that it may be beneficial to directly block cyclosporine's constriction of blood vessels supplying the kidneys rather than to rely on dose adjustment alone. Scientists suspect this vessel constriction is the basis for the observed kidney toxicity.

Some researchers are testing drugs that specifically inhibit the synthesis of thromboxanes, substances made by the body that cause vessels to constrict. Two preliminary clinical trials of such drugs have just begun, says bennett. In addition, blood-pressure-lowering drugs called calcium channel blockers dilate these blood vessels -- but they also raise the level of cyclosporine in the blood. Although Bennett says the use of such drugs along with cyclosporine appears promising if cyclosporine levels are precisely monitored, he and his co-workers have been looking at the "vehicle" solution in which the water-insoluble cyclosporine is dissolved before use.

Alcohol and olive oil are two standard vehicles used by physicians, but Bennett and colleague Vickie Kelley at Brigham and Women's Hospital in Boston think that omega-3 fatty acids found in some fish oils may offer a two-fold advantage. Fish oils have attracted attention recently for their potential lowering of heart disease risk (SN: 11/28/87, p.342). Bennett says they apparently reduce thromboxane synthesis and the clumping of blood-clotting cells called platelets. And Kelley has evidence that dietary fish oils also suppress the immune system. Their animal studies show that dissolving cyclosporine in fish oil "markedly reduces" kidney toxicity, and that even giving fish oil supplements separately decreases side effects, Bennett says. He doesn't advocate that fish oil now be taken with cyclosporine, but does expect a two-year clinical trial currently underway to reveal whether administration of fish oil will lead to lower effective doses of cyclosporine and less kidney toxicity.