Pancreas-Kidney Transplantation: Drugs

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Immunosuppressant Drugs

As mentioned earlier, the first transplants were performed using corticosteroids, azathioprine (6-mercaptopurine). While somewhat effective in suppressing immune response, they suffered from a lack of specificity, suppressing the total immune system, and yet not entirely stopping rejection.

The corticosteroids (Prednisone and others) are among the oldest anti-rejection drugs; as noted earlier, these drugs work principally by reducing the inflammatory response, and slowing the complement cascade. These drugs also affect virtually every other aspect of immune response, including leukocyte and lymphocyte proliferation, monocyte and basophil counts, and cellular communication. Unfortunately, corticosteroids also have some of the more severe side-effects. While they are still widely used, their use at lower dosages, and lowering doses much sooner, is the current trend; a few centers are removing corticosteroids entirely—at least for some patients.

In 1970, a new immunosuppressant was discovered in a soil fungus in Norway (Beauveria nivea) and called Cyclospoine-A (brand names Sandimmune, and later, Neoral). Approved for wide use by the US FDA in 1983, cyclosporine, while it seems to have several immunosuppressant effects, principally interferes with the action of helper T-lymphocytes.

New immunosuppressant agents continue to be developed. In 1984, a substance was isolated from a soil bacterium (Streptomyces tsukubaensis) found near a mountain outside Tokyo. The refined drug was named tacrolimus (Prograf) and was approved by the US FDA in 1994. Tacrolimus seems to work by interfering with the ability of interleukin-2 to communicate with the T-cell receptors, suppressing the activation and replication of the T-cells.

Cyclosporine and tacrolimus are both the same broad class of drug: “calcineurin inhibitors”. Calcineurin is a cellular protein that assists enzyme functions and the complex processes of IL-2 in signaling between immune cells. They are quite effective at immunosuppression, but they are also toxic to nerves, kidneys, and can cause diabetes.

Another drug, Rapamune (sirolimus), was approved 09/15/99 by the FDA for manufacture and distribution by Wyeth-Ayerst. This drug, like the others, must be used in combination with other drugs to suppress several actions of the immune system. However, sirolimus is a completely different class of drug from the calcineurin inhibitors; it is a ‘TOR’ (target or rapamycin) inhibitor. This drug also interrupts IL-2 synthesis and signaling, but at a different point in the chain of events than the calcineurin inhibitors. It seems to be far less toxic to tissues than the other drugs.

Azathioprine, mentioned earlier, is still in wide use (brand name Imuran). Azathioprine and a newer drug, Mycophenolate Mofetil (CellCept), have a similar end result, though the two have different ways of achieving it. The outcome in both cases is the suppression of white blood cell proliferation (B-cells, T-cells, and macrophages). One drawback to Imuran is that, while it does suppress the white cells normally activated in an immune response, it also can suppress red cell and platelet production, which can be an unwanted side-effect. In 1995, CellCept was approved by the US FDA for use in kidney transplants, and in subsequent years has been approved for use in other organ transplants. CellCept works by limiting the division and development of white blood cells, but seems to have little effect on other bone-marrow products. The major side effects are gastrointestinal discomfort, and the possibility of a lowered white count, usually reversible with reduced dosage. An uncommon, but very serious, side-effect of these two, particularly of CellCept is the potential for post-transplant lymphoproliferative disorder, essentially a type of white blood cell ‘cancer’. When the white blood cells begin to reproduce out of control, then the drug usually must be stopped to save the patient’s life. The transplanted organ is in serious jeopardy if this should happen.

Computer Model of
Zenapax

A relatively new development in immunosuppression is the use of monoclonal antibodies to fight tissue rejection. OKT3, ATGAM, Simulect, and Zenapax all function by binding to receptor sites on the T-cells, thus preventing their activation by the transplanted tissue antigens; they do not suppress the entire immune system. While the body can manufacture antibodies against the OKT3, Zenapax is less "visible" to the human immune system, and is much less likely to provoke another immune response. The fact that these drugs operate on the T-3 and T-4 receptors gives them perhaps the highest specificity of all immunosuppressants, with a very small occurrence of side effects. OKT3 and ATGAM are used primarily to counter an acute rejection episode; another medication very similar to ATGAM that is used in acute rejection episodes is Thymoglobulin— anti-thymocyte globulin. Zenapax, on the other hand, is used from the time of transplantation, continuing for about ten weeks in order to prevent early rejection episodes.These drugs are quite powerful and are not suited to maintenance immunosuppression; they are used almost exclusively to treat patients in the first few weeks after transplant, or to stop acute rejection episodes.

New drugs are always in development, and the list above is far from complete, but it does cover some of the most widely used anti-rejection drugs. A new drug, ISAtx247 manufactured by Isotechnika of Edmonton, Alberta, Canada entered Phase-1 clinical trials August 28, 2000. The drug is reportedly 3 time more potent than Cyclosporine and at the same time 5 times less toxic. Clinical trials continue. Other new or investigational drugs include variations on older formulations, as wells as entirely new classes of immunosuppressants. Included are Gusperimus (15-deoxyspergualin), brand name Spanidin, an intravenous immunosuppressant that suppresses production of cytotoxic T cells, neutrophils and macrophages; Medi-500 (formerly T10B9), an intravenous monoclonal antibody targeted against the human T cells; FTY 720, an oral myriocin derivative rthat alters lymphocyte infiltration into grafted organs; Medi-507, an intravenous humanized antibody directed against the CD2 T cell; HLA-B2702 peptide, an intravenous human peptide that blocks the action of NK cells and T-cell- mediated toxicities. Of those drugs mentioned, FTY 720 is perhaps the closest to completetion of clinical trials.

Other Drugs

Many other medications that are not immunosuppressants are used to complement the anti-rejection drugs.

Bactrim (trimethoprim/sulfamethoxazole or TMP/SMZ) treats bacterial infections, particularly Pneumocystis carinii pneumonia. Bactrim is usually taken long-term by transplant patients. Levaquin (levafloxacin) or one of the erythromycins can be used to prevent infection following dental work. A wide variety of antibiotics—vancomycin, clindamycin, tobramycin, many cephalosporins and quinolones—are available for use; the drug chosen is based on the location of the infection and the specific organism causing it.

Cytovene (gancyclovir), or Valcyte (valgancyclovir), can be used to treat cytomegalovirus. Cytomegalovirus can affect numerous part of the anatomy, causing retinitis, gastroenteritis, and pneumonia. Other antiviralscan be used in some cases, but viruses are particularly difficult to handle under immunosuppression.

A number of anti-fungal drugs can be used to treat yeast or fungus infections. Among these are Mycostatin (nystatin), Mycelex (clotrimazole), Diflucan (fluconazole), and Nizoral (ketoconazole).

Other minerals and supplements may be needed to maintain the electrolyte balance, and to replace numerous elements lost through a bladder-drained exocrine duct of a pancreas transplant.

Since several of the required immunosuppressants may cause hypertension, blood pressure medication may be required, although calcium-channel blockers like Cardizem and Procardia can propitiate the bioavalability of some immunosuppressants, requiring a smaller dose to acheive the same blood level. Also, since some immunosuppressants can elevate cholesterol and other blood lipids, a medication to lower cholesterol may be added to your regime. Lasix or other diuretics may be required if the patient is retaining fluid.

No matter what combination of drugs is prescribed, it is important to understand that this drug plan has been tailored for you and for you alone. Never change anything about your medication, the dosage, the time that you take it, whether you take it with or without food, anything at all, without consulting your transplant team! A change in one drug may require concomitant changes in several other drugs. Adjustments will be made by the transplant team in response to the levels indicated by your periodic labwork. Never add over-the-counter products or herbal remedies without consulting your transplant team. Many so-called "safe and natural" products can have disastrous effects when combined with your immunosuppressant drugs.

The interrelationships between all these very powerful drugs are multifaceted and quite complex, and any unplanned changes can have serious consequences. Compliance with your drug regime, long-term, is perhaps the single most important facet in maintaining the health of the transplants.