Part 3 • Medical Therapy and Surgical Intervention Chapter 7 Philosophy, Goals, and Approaches to Medical Therapy

the starting dose of 10 mg/kg/day sets into motion the mechanisms leading ultimately to the changes noted histologically. Some have found that changes in renal function can develop even at lower starting doses of ciclosporin.128 However, most recent reports from investigators treating autoimmune conditions (other than uveitis) with lower starting and maintenance doses of ciclosporin have been heartening because little or no alteration in renal function associated with this agent has been noted.111 Feutren and Mihatsch129 reviewed 192 renal biopsy specimens from patients treated with ciclosporin for a variety of conditions, including diabetes mellitus, Sjögren’s syndrome, and uveitis. It was found that three independent variables distinguished the 41 patients with ciclosporin-induced nephropathy from those free of nephropathy: a higher initial dose of ciclosporin, a larger maximal increase in the serum creatinine concentration above baseline, and age. Therefore it has been suggested that to reduce the risk of nephropathy a dose of 5 mg/kg/ day should be used, and serum creatinine levels should not rise more than 30% over the patient’s baseline level. Also, a retrospective analysis of 1663 patients who had undergone renal transplantation and were receiving longterm ciclosporin therapy demonstrated that progressive toxic nephropathy did not occur.130 The addition of bromocriptine131 to the regimen permits the use of a lower dose of ciclosporin, with the hope that a similar therapeutic result with less toxicity would be achieved. However, this approach is not being used. Ciclosporin interacts with many agents, and one must be very cognisant of this. The concomitant use of NSAIDS with ciclosporin will almost ensure decreased renal function. Other medications that can interact with ciclosporin can be seen in Box 7-2.

We and others132,133 have reported that ciclosporin can be found in the anterior chamber of patients receiving systemic medication, and in the CSF as well. A recent report by Mora et al.130 suggested that tear-fluid levels of ciclosporin correlated with systemic levels of the medication.

Opportunistic infections have not been a major problem in patients with uveitis treated with ciclosporin. Certainly,

Box 7-2  Some medications that may interact

pharmokinetically with ciclosporin

Amiodarone

Carbamazepine

Clarithromycin

Corticosteroid

Diltiazem

Doxycyclin

Erythromycin

Fluconazole

Itraconazole

Ketoconazole

Nicardipine

Nifedipine

Phenytoin

Protease inhibitors

Rifampin

Verapamil

Theophylline

some risk is present if patients receive other immunosuppressive agents combined with ciclosporin. A trend was observed toward less renal toxicity in patients who received combined ciclosporin/steroid therapy rather than ciclosporin alone.134 We have noted that patients with uveitis treated with ciclosporin demonstrate appropriate immune responses both to new antigens and to old ones requiring a ‘recall’ response.135 Therefore, vaccination can apparently be performed on patients treated with this medication, but preand post-immunization titers should be checked. Further, to date, no lymphomas or other ciclosporin-related neoplasms have been seen in our patients. The incidence of lymphoma observed in graft recipients treated with ciclosporin was 0.3%.100 Most disease develops in the first few months and has mainly been associated with multiple-drug regimens. Ciclosporin may cause CNS changes: the most common we have seen are tremors (at higher dosages). It has been suggested that Behçet’s patients receiving ciclosporin may develop CNS problems, but that was not seen in the original randomized study in Japan. However, it has been reported to cause headache, mood alterations, and rarely leukoencephalopathy, seizures, visual disurbances, psychiatric problems, and motor and speech disturbances.136

Tacrolimus

Mode of Action

Tacrolimus (FK506), an immunosuppressive agent with a molecular weight of 822 Da, was isolated from the broth of Streptomyces tsukubaensis137,138 (Fig. 7-12) and is believed to have essentially the same mechanism of action as ciclosporin.102 One difference is that the immunophilin that binds with tacrolimus is FK506-binding protein (FKBP) instead of cyclophilin. It suppresses the formation of mRNA for IL-2, as does ciclosporin, but at an effective in vitro therapeutic concentration about 100 times less than that of ciclosporin.138 Using a dose 10–30 times smaller than that of ciclosporin, tacrolimus was found to be effective in preventing the development of experimental autoimmune uveitis in rats139 as well as in monkeys.140 However, the toxic effects (see later discussion) are seen at therapeutic doses, so that the decreased therapeutic dosage appears to have little benefit. It is metabolized by the cytochrome P450 system.

OMe

O

Me Me

OH

Figure 7-12.  Structure of tacrolimus (FK506). (From Schreiber SL, Crabtree GR. The mechanism of action of ciclosporin A and FK506. Immunol Today 1992; 13: 136.)