Correspondence

Cyclosporine in Severe Ulcerative Colitis

N Engl J Med 1995; 332:127January 12, 1995

Article

To the Editor:

In the study by Lichtiger et al. (June 30 issue),1 we were surprised by the high frequency of neurologic side effects in the cyclosporine-treated patients. In a review of 3000 recipients of kidney transplants and 800 recipients of bone marrow transplants treated with cyclosporine, the incidence of seizures was 1.5 percent and 5.5 percent, respectively.2 As Lichtiger et al. suggest, cyclosporine neurotoxicity may be related to hypocholesterolemia or hypomagnesemia; other postulated mechanisms include hypertension and increased permeability of the blood–brain barrier. Of special interest is the possible toxicity of the solvent in which cyclosporine is provided or concomitant parenteral nutrition with a lipid solution.3,4 One of the patients in the cyclosporine group received total parenteral nutrition. Was this the patient who had the seizure?

The main determinant of the toxic effects of cyclosporine is a high blood cyclosporine concentration.2 This emphasizes a bias of the study performed by Lichtiger et al. They measured blood cyclosporine concentrations using two different radioimmunoassays. The reported mean concentrations were higher than those considered therapeutic, and the wide ranges reported suggest that the concentrations varied widely. This variability may be explained by drug interactions with cyclosporine. In 2 of the 11 patients treated with cyclosporine hypertension developed that was treated with calcium-channel blockers. The majority of these antihypertensive drugs, especially diltiazem, inhibit hepatic cytochrome P-450 and increase blood cyclosporine concentrations. Many antibiotics (prescribed in eight patients in the cyclosporine group) and histamine H₂-receptor antagonists have a similar effect.5 We think that more information about drug monitoring and concurrent therapies may help to determine the minimal effective dose of cyclosporine and thus to minimize the toxic effects of this promising therapy for patients with severe ulcerative colitis.

François Vincent, M.D.
Thierry-Alain Bensousan, M.D.
Institut Gustave-Roussy, 94805 Villejuif, France

5 References

1. 1

   Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-1845
   Full Text | Web of Science | Medline

2. 2

   O'Sullivan DP. Convulsions associated with cyclosporin A. BMJ 1985;290:858-858
   CrossRef | Web of Science | Medline

3. 3

   Hoefnagels WA, Gerritsen EJ, Brouwer OF, Souverijn JH. Cyclosporin encephalopathy associated with fat embolism induced by the drug's solvent. Lancet 1988;2:901-901
   CrossRef | Web of Science | Medline

4. 4

   De Klippel N, Sennesael J, Lamote J, Ebinger G, de Keyser J. Cyclosporin leukoencephalopathy induced by intravenous lipid solution. Lancet 1992;339:1114-1114
   CrossRef | Web of Science | Medline

5. 5

   Vincent F, Glotz D, Kreft-Jais C, Boudjeltia S, Duboust A, Bariety J. Insuffisance rénale aiguë chez un transplanté rénal traité par cyclosporine A et métronidazole. Therapie 1994;49:155-155
   Web of Science | Medline

To the Editor:

Lichtiger et al. do not mention the method of randomization used to assign patients to the cyclosporine or placebo group. This forces the reader to guess whether the methods used were appropriate and whether a bias associated with treatment assignment may have affected the outcome of the study.

S. Elizabeth Whitmore, M.D.
Johns Hopkins University, Baltimore, MD 21287-0900

Author/Editor Response

Dr. Lichtiger replies:

To the Editor: The high incidence of neurologic side effects to which Vincent and Bensousan refer must be interpreted with caution. The most common side effect of cyclosporine is paresthesia.1,2 It was often subjective and did not warrant termination of the drug in any of our patients. The single patient who had a grand mal seizure had hypocholesterolemia, which is known to increase central nervous system concentrations of cyclosporine, thereby precipitating seizures.

Blood cyclosporine concentrations were measured every other day, and the dose of cyclosporine was adjusted as needed to maintain the therapeutic concentrations mentioned in our paper. Although various histamine H₂-receptor antagonists, antibiotics, and other drugs do inhibit the cytochrome P-450 system, there was no clear relation between the administration of those drugs and the need for adjustments in the cyclosporine dose in our patients.

The patients were randomized sequentially in a manner predetermined by Sandoz. Medication was prepared by the hospital pharmacy and labeled with only the patient's identification number and date. The physicians performing the evaluations never had access to the randomization code or to the medication.

Simon Lichtiger, M.D.
Mt. Sinai School of Medicine, New York, NY 10029

2 References

1. 1

   Palestine AG, Nussenblatt RB, Chan CC. Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 1984;77:652-656
   CrossRef | Web of Science | Medline

2. 2

   Brynskov J, Freund L, Rasmussen SN, et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:845-850
   Full Text | Web of Science | Medline

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2. 2

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