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Question:

From North Carolina, USA:

I am being considered for the Edmonton protocol [for islet cell transplantation]. What the side effects most often occurred with the use of Prograf and Serolimus? I also want to know if there have been any studies regarding these drugs and pregnancy. They have told me I can never have children. Dr. Shapiro told me that this was more of a liability issue. Are new anti-rejection drugs being developed that target just part of the immune system? Do you think I will ever be able to come off these drugs if a better treatment arises?

Answer:

The report by James Shapiro and others on Islet Transplantation in Seven Patients with Type 1 Diabetes, which appeared in the July 27th issue of the New England Journal of Medicine, represented a very significant step forward. Since submitting this data, the team will have added significant additional experience, and for that reason, they should be the definitive responders to your questions.

Serolimus and Tacrolimus (Prograf) are two immunomodulatory drugs which inhibit the action of interleukin-2, a substance which stimulates the production of Th-1 or destructive lymphocytes. In the doses used in the Edmonton study, they provoked only minimal side effects limited to minor superficial buccal ulceration which cleared with the reduction of the Serolimus dose. These two drugs have, however, been more widely used in other transplant programs, and other side effects have been noted. Serolimus, for instance, can produce headaches, a lowered blood platelet and white cell count as well as a rise in blood lipids. Tacrolimus can result in headaches, diarrhoea, and tremors. Both have a rather wide range of incompatibility with other drugs.

It seems that the pregnancy issue is an important one, and certainly, exposure of a fetus to either of the above two drugs is specifically contraindicated. At present, no one really knows how long you might have to continue with this immunosuppression. This in turn raises two other issues: that of exploring adoption and the alternative of making one further major effort to achieve good blood glucose control. The two criteria for inclusion in the first part of the Edmonton trial were intractable hypoglycemia and so-called brittle diabetes. You don't say into which category you fall, or whether your motivation is mainly to be freed of the tyranny of current routines. In any case, there are many centers that would urge you to try again for good control with some of the new regimens that will soon be available, e.g. lispro insulin with once a day glargine and using a FreeStyle meter for measuring glucose, or one of the versatile new insulin pumps, perhaps with a GlucoWatch, which is expected to be available early next year. Success, with either of these programs, would not only permit pregnancy but would minimise risks to the baby.

Finally, you may be encouraged to know that, as the details of both allo- and auto- immunity have been worked out in recent years, a considerable number of new drugs are being involved which do target specific parts of the immune system. One of these is Zenapax (Daclizumab) which was also used in the Edmonton trial (and is also being used to try to prolong the honeymoon period). This inhibits the IL-2 receptors with an end result not very different to Serolimus. Then there are the vaccines like the 9-23 segment of the B chain of insulin, or another short peptide called DiaPep277 which appear to promote activation of the Th2- type lymphocytes which are protective. Some Vitamin D3 analogues have a rather less clear role in this process. In addition to antigen and cytokine based therapies, there are others that use monoclonal antibodies like anti CD3.

I am sorry if this sounds all very confusingly technical, but the essence is to show you that there is a lot going on in the field.

DOB

DTQ-20000915013528
Original posting 1 Nov 2000
Posted to Transplants

  
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Last Updated: Tuesday April 06, 2010 15:09:14
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