CYCLOSPORIN --------------------------------------- (1) Erythema multiforme (2) Vasculitic ulcer (3) Exfoliative dermatitis (4) Brown-recluse spider bite (5) Grapefruit juice (to lower the dose of cyclosporin) ------------------- ERYTHEMA MULTIFORME ------------------- I certainly agree that we don't want to fix the skin and wreck the kidneys. Fortunately, short term CyA (eg. for acute TEN or Stevens-Johnson, bad poison ivy, etc.) is very safe in that regard. As a practical matter irreversible renal toxicity is something that can be seen after LONG term Rx with CyA, and the risk of this can be greatly reduced by following the guidelines in the package insert (eg. watch for other drugs that interfere with CyA, monitor the BP q 2 wks at first, then q month, and monitor the creatinine - always comparing it with the BASELINE level pre-CyA and stopping or cuiting back the CyA if creatinine rises more than 30% above baseline). Must say that in some acute cases I don't waste a few days getting baseline creatinines - I start the CyA and send the patiient down to the lab for an immediate creatinine, and get another in a couple of days, then chenk q 2 weeks for a month or two if they need long term Rx. If someone is only going to be on CyA for a couple of weeks (eg. poison ivy) and is otherwise healthy and has no Hx of renal or BP problems I sometimes don't do the creatinine, but I always check the BP before Rx and a week later. KC Smith MD FRCPC ----------------- I haven't use CyA as a "single bolus" - don't know how that would work. In my experience with E. multiforme it usually takes a day or two to produce good results, so I'd guess bid doses for at lest 2-3 days would be the minimum needed to get a good result, and as a practical matter once they've improved I'm inclined to leave them on CyA for a couple of weeks at least to reduce the risk of relapse. Anyone got experience with true "bolus" doses, or courses shorter than a couple of weeks for E. multiforme? KC Smith MD FRCPC ----------------- Certainly CyA is a good choice for people with relative contraindications to prednisone; and also for people who can afford CyA and prefer it when they've read the information brochures about the 2 drugs. If I had poison ivy I'd reach for the CyA, because the consequences of AVN or disturbances of judgement on prednisone would be great in my case. And CyA does not cost me anything, because I keep a stockpile of it at the office. I think that once you have a lot of experience with CyA, you'll find that it would take a lot of nerve NOT to use it for things like Stevens-Johnson; and you'll be queasy when you order prednisone - knowing that in many cases CyA would be safer and better tolerated. KC Smith MD FRCPC ------------------ Here is the medline search results on your question. The evidence is peer reviewed anecdote. Is there any interest in a prospective study? Hewitt J Ormerod AD Toxic epidermal necrolysis treated with cyclosporin. Clin Exp Dermatol (1992 Jul) 17(4):264-5 Toxic epidermal necrolysis (TEN) is a severe life-threatening disorder which has many features in common with graft-versus-host disease. However, immunosuppression with steroids gives disappointing results and is possibly detrimental. We treated two patients who had TEN with a combination of cyclosporin and steroids which resulted in an apparent halt to the evolution of the disease, and a further relapse was aborted using cyclosporin in one of these patients. We feel that the use of this drug in the early treatment of TEN where it is used as a specific therapy aimed at the primary immunopathological events and is used in conjunction with the supportive care patients require, needs to be further evaluated. Rhett Drugge, M.D. ------------------ The nephrotoxicity in the short run is I think over-rated, especially since it appears that early reductions in GFR are related to reduction in renal blood flow, which in turn normalizes after CyA discontinuation. It's later that progressive and irreversible loss of GFR becomes more of a concern, so that it may indeed be a good short-term steroid alternative, although it's as always critical to point out that there are no substantive reports of extensive short-term experience with CyA, so caution is certainly still warranted. COST is still the big issue with me: my "prescriber profile" is already outrageous without adding $250 per course of CSA per case of poison ivy! Mark Ling, M.D., Ph.D. ---------------------- I wrote a review of cyclosporin in dermatology several years ago for the first edition of Current Opinion in Dermatology. I wasn't awqare at the time that the Index Medicus does not carry a reference until a journal has been in print for at least three years. Current Opinion has some of the best and most current reviews. I highly recommend it. Here's the reference: Ely, H., Recent developments in dermatologic uses of cyclosporin and amelioration of renal toxicity with pentoxifylline, Current Opinion in Dermatology 1993:223-230. A review with annotated references As you would gather from the title Trental completely abolishes the bad renal side effects of cyclosporin. The full story is in the review. CsA, especially when used for a short course, is especially useful for toxic epidermal necrolysis, pyoderma gangrenosum, and erythema multiforme major. Other excellent responders include Behcet's disease, lichen planus, and epidermolysis bullosa acquisita. Of the diseases mentioned I think TEN is where we should think of CsA first rather than last since there may not be much time to save the patient in a fulminant case. Haines Ely ---------- ---------------- VASCULITIC ULCER ---------------- I have a 70 yo female patient with an ill defined vasculitc 15 mm ulcer on her R tibia. Bx shows vasculitis but DIF is neg, studies for cryoglobulins, Lupus anticoagulant and antiphospholipids are neg. ANA and associated antibodies - neg. No findings for pyoderma gangrenosum, and recent colonoscopy is normal. LFTs Normal. Fungal cultures taken by curette are pending. Responded partially to prednisone but poorly tolerated and has moon facies now. Currently on Dapsone 100 mg qd, prednisone 20 qd, and repeated triamcinolone injections around ulcer. Is this a candidate for CyA or would others treat differently? Jerry Eisner ------------- At cursory look this patient may respond well to CsA for two reasons: the cushingoid changes and the decreased wound healing wouldn't be an issue if you substituted CsA for prednisone. The catabolic effects of glucocorticoids are not present with CsA. Clearly you may want to first consider antimalarials such as the triquin combination if her visual fields are intact. I consider both of these agents much more effective than dapsone in the control of vasculitis. Rhett Drugge ------------ I'd probably try Trental 400 - 800 tid, perhaps with dexamethasone 0.75 mg qAM, +/- Ticlid and ASA before CyA. KC Smith MD FRCPC ----------------- Already tried Trental, no go. Haven't tried ASA, don't usually use together with prednisone, due to ulcer potential. What do you think about Plaquenil? I already know her G6PD is ok :>) Rhett, RE:triquin. Isn't Atabrine off the market? Should I try Plaquenil alone first? ( I also reviewed your note of April 14 regarding triquin and will check the Electronic Textbook of Derm). Jerry Eisner ------------ Certainly, as plaquenil will give you the same effect as the antimalarial cocktail, triquin. The combination lowers the toxicity of any one agent. If you have trouble getting it contact me. My pharmacist has it already prepared in capsules. Rhett Drugge, M.D. ------------------ ---------------------- EXFOLIATIVE DERMATITIS ---------------------- I have recently used Cyclosporine (Sandimmune) in an adult male with exfoliative dermatitis with little or no benefit. He had been moderately controlled previously with PUVA and occasional injections of Kenalog. (Yes, I am aware of rare reports of SCCa in patients on Cyclosporine following PUVA Rx.) Philip Hughes, M.D. ------------------- What is the underlying disease, skin or otherwise, causing his exfoliative dermatitis. We might then better understand why Sandimmune would or would not be effective, and why PUVA/Steroids are somewhat. Did he have a biopsy or history or atopy or psoriasis or whatever? Diane Thaler ------------ I believe this patient is atopic, with prurigo nodularis from time to time overlying the chronic eczematous dermatitis when he flares. I don't recall doing a skin biopsy. Philip Hughes, M.D. ------------------- Did you obtain a Cyclosporine blood level? Activity can be compromised the extreme lipophilicity of this drug. Serum levels greater than 50 micrograms per ml are usually required for efficacy. Rhett Drugge ------------ Just had an erythroderma patient clear nicely on Neoral. He had no improvement last year on Sandimmune. (Too bad a non-Sandoz generic isn't available. At least Neoral doesn't have a reference to Sandoz in the name.) Philip Hughes, M.D. -------------------- ------------------------- BROWN-RECLUSE SPIDER BITE ------------------------- I was wondering if anyone has tried it in a short pulse for brown recluse spider bite reactions. I can't recall seeing any articles on this possibility. Antivenom and Dapsone treatment appear the most promising, but systemic and IL steroids are also used. Dapsone probably acts via it's effects on leukocytes so I wonder if CyA, suppressing certain lymphocyte subsets, would be of much use. Any thoughts? Kip Cullimore ------------- To the extent that this problem is mediated by PMNs I'd be more inclined to try Trental 400 - 800 tid than CyA. What I'd like to see would be an animal model of brown recluse bite where CyA, Trental, etc. could be tried. Seems to me that Lloyd King (?) at Duke is the expert on Brown Recluse (gave us a great lecture when he visited my residency program). Wonder if he knows of an animal model? Seriously - CyA is right up there with Accutane and MTX - a very useful tool, but if you want to use it you'd better read the package insert - and go beyond that into the original literature to really understand the drug. ------------- MISCELLANEOUS ------------- It is very effective in psoriasis, seborrheic dermatitis, atopic dermatitis, drug eruptions and graft versus host disease. Pityriasis rubra pilaris doesn't respond. I find my patients who need CSA the most are the ones with the worst protoplasm eg bad psoriasis + morbid obesity+ diabetes. I've had a number with decreased renal fxn and elev. BP refractory to medication. I suppose that if I used it more liberally then healthier patients would get it and would do better on it. I'll have to think about this. A tip (that you probably know already) that I find useful is to give the CSA with grapefruit juice daily. The naranjin in the juice inhibits intestinal cytochrome (I forget which subtype) and raises CSA levels. Patients can then take less drug to get the same effect and save $$. Guy Webster ----------- ---------------- GRAPEFRUIT JUICE ---------------- It contains naragenin which either by itself OR a metabolite inhibits the most common isozyme of cytochrome P450 seen in our USA. In fact, the add for Neoral (CsA) in British magazines warn patients not to take their medicine (CsA) with grapefruit juice. Interesting, Yes! -- Patrick Carrington, M.D. -------------------- there are a number of excellent articles in the Oct.1966 ed. of infections in medicine...one is how grapefruit juice will inhibit the p450 enzymes...like seriously!...increasing seldane, ketoconazole etc to very high levels...another is a fascinating one about a fish that can swim up inside the urethra while you're out in the water...(ouch!)...check it out!... steve emmet -------------------- I have a couple poor psor patients who are maintained on 200/day of cyclosporin and 1 glass of GFJ/day. It cuts their CSA bill in half. Levels are stable too. Guy webster -------------------- Great idea. I've used ketoconazole and/or erythromycin for the same thing, as do renal transplant surgeons/nephrologist. Grapefruit juice is cheaper, but the taste: Patrick R. Carrington -------------------- I would remind you that cyclosporine is, in my opinion and experience, the "magic bullet" for E. multiforme -- I've had patients who would have gone to the burn unit in the past, but with cyclosporine they stayed home. Don't save it for a "last resort" when the patient has lost 90% of their skin - nothing will help then. Give it STAT. before they leave the office, or at least before the day is over. Kevin C. Smith MD FRCPC -------------------- Ditto! I, too, feel a 'window' of opportunity exists for early use of CsA in EM/TEN. If one waits too long (3-5 days +/-) then the burn unit may be lifesaving. Patrick R. Carrington -------------------- Also works almost instantly for fixed drug eruption (had a case 2 weeks ago). I give 5-10 mg / kg as a STAT dose in the office, then around 5 mg / kg day for a few days, by which time they've improved, then 1-2 mg / kg day for a week or two, then stop and see what happens. So far no relapses. I've never admitted anyone for anything in 8 years, just lucky I guess (plus I'm fairly quick and aggressive with the outpatient treatments, and generally I think patients are better off at home with their own germs, eating their own food, than in hospital). Kevin C. Smith MD FRCPC -------------------- I don't do any labs for cyclosporine 3 weeks or less, unless there is some indication (eg. Hx of diabetes, hypertension). Kevin C. Smith MD FRCPC -------------------- Re: CsA Labs Interesting, KS, that you don't do any labs for 3 weeks or less. Let me get this straight: this is in patients starting @ STAT 5-10mg/kg at once then 5 mg/kg/d for several days, then 1-2mg/kg/d for weeks. Is that right? If so, you have exonerated me for using CsA both at LSU Med Ctr and at Univ Ar Med Sciences WITH labs while being 'ridiculed' by my colleagues. Patrick R. Carrington -------------------- Your co-workers shouldn't ridicule you for doing labs during a short course of treatment with cyclosporine (or for using cyclosporine -- some day they'll have a tough case on their hands and you'll be the only one around who's comfortable with cyclosporine -- they'd better hope you're in town that day!) but the yield of useful information is very low, so I stopped. For acute things like TEN, Stevens-Johnson, bad contact dermatitis, waiting for labs before starting cyclosporine would largely eliminate the benefits of using it, and the followup lab tests would come back at about the same time that the cyclosporine was being stopped anyway. If I'm not sure it will be a short course (eg. some E. multiforme cases) I'll grab a creatinine the same day I start the cyclosporine, plus maybe a CBC and SGOT; and maybe a creatinine again when they come back in a week if it looks like they'll need more than a couple of weeks of cyclosporine. I should add that for longer courses of treatment RIGID ADHERENCE TO THE TESTING PROTOCOL AND MONITORING BLOOD PRESSURE IS MANDATORY. Cyclosporine is a drug which MUST be carefully monitored and followed up on when used long term. The dose MUST be reduced or stopped if creatine rises 30% above baseline, and the patient MUST be asked at every visit about other meds and things like grapefruit juice (forbidden for my patients, because I can't control the batch-to-batch potency of the grapefruit juice component that interferes with cyclosporine elimination). With most drugs problems tend to happen early - with cyclosporine problems accumulate and get worse as time goes on, and if someone is on cyclosporine long enough they will almost certainly get some sort of abnormality (usually renal). However, for a couple of weeks (3 weeks max) cyclosporine is very well tolerated and easy to use. Kevin C. Smith MD FRCPC -------------------- In the rxderm-l, I read about the use of cyclosporine for drug reactions. In germany, as far as I know, cyclosporine isnīt admitted for this use, nor recommended in the dermatologic literature. Are there greater experiances in USA, or is the use only episodic? Frequency of TEN after Co-trimoxazol in germany is reported to be about 0,3/million days of therapy, being the most frequent cause of TEN (12 of 47 cases of TEN in the study), so I donīt use this drug for acne. Andreas Eisenmann -------------------- Kevin, what labs do you do to follow for someone on cyclosporin on a chronic basis (say for psoriasis)? Mark Naylor, M.D. -------------------- creatinine & blood pressure q2wks for about 2 months, then if stable q-month. Thats it . The yield on repeat CBC and LFT is so low I quit a long time ago. By the way, had a machinist in with bad hand dermatitis Thursday and today (Monday) she was VERY pleased with the improvement on cyclosporine 100 mg tid. I've started her on PUVA, and plan to stop the cyclosporine in another 7 days. Her brother had been on prednisone, so she was very appreciative of the relative lack of side effects of cyclosporine. Before Rx cyclosporine for any duration I discuss the medication (they'll get a handout at the drugstore anyway, so I might as well get in the first word.) I explain that its safer and easier to take than prednisone short-term, and probably long term also if need be; and I discuss the need for monitoring if taken long term. These cases usually improve with PUVA or UV-A ~10 - 15 J 2-3 times a week long term, together with Prevex-HC cream applid sparingly after every hand washing and mometasone ointment HS to the most severely involved areas, with ciclopirox (Loprox) with 1% HC to the nailfolds tid to deal with paronychia. Its very useful to photograph the hands before treatment - this will give you and the patient a better impression of how they are doing, and motivate long-term compliance. Without photos you might not realize that they are improving, and quit too soon. "Glove hyperpigmentation" has not been a problem for my patients - not something they complain about anyway. I've only got one patient on long-term cyclosporine for hand dermatitis, and she can't come on a regular basis for UV-light treatment. Kevin C. Smith MD FRCPC -------------------- why do you think that the way of dealing with novel therapeutic approaches should be different here? I always believed that our societies as well as the *medical community* have more in common than substantial differences. But I guess that is not the point your question targeted. You might want to know why we are generally a kind of reluctant towards CSA. Surely I only can answer for myself and not for all my colleagues. We learn at the universities that you always should find a *reasonable* relationship between drug action and possible side effects. So we knew CSA as high dose treatment (with considerable side effects, of course) in transplant patients, and later, as one of the *last choice* drugs kept in the closet for severe psoriasis that otherwise couldn't be managed. Then, the company tried to push CSA for milder forms of psoriasis but failed, because a) the opinion leaders didn't recommend it and b) of the rebounds. >From that history, maybe it is a bit more understandable that there is a sort of caution to consider CSA as first line therapy and to prefer steroids with the decades of experience with it. I even tried to prevent patients from getting into a clinical trial of CSA in atopic dermatitis. But we all are able to learn, and you can book it as a personal success and an effect of this list: we got a young woman with Stevens Johnson after oral penicillin to the ward yesterday and... began a therapy with cyclosporine! Sure my boss and we residents knew that high doses of steroids always have been more or less a *what else should we do* decision, but now we were encouraged also by the list discussion to take the other way this time. Today, the symptoms are at least not in progression. Hans J. Kammler -------------------- A component of grapefruit juice, as yet unidentified, inhibits cytochrome-P450 in the gut wall and to a lesser extent in the liver, reducing metabolism of cyclosporine (and also of midazolam, Halcion and some dihydropyridine calcium channel blockers) leading to higher blood levels and increased area under the curve. I didn't know there was P-450 in the gut wall. Learn something new every day! If you're using Halcion as a pre-anesthetic sedative it might be a good idea to make sure the kid didn't have grapefruit juice for breakfast! ref: Lancet 15 April 1995; 955-6 Clin Pharm Ther May 1995; 485-91 Clin Pharm Ther March 1995; 318-24 Transplantation 15 July 1996;123-5 Remember, you can get free unlimited medline searches and look this kind of stuff up for yourself at: www.medscape.com www.healthgate.com Kevin C. Smith MD FRCPC -------------------- According to a lecture I attended at U.T. Southwest by Dr. CLark Gregg, the component is Naringenin, which inhibits CP450 subtypes 3A4, 1A2 and 2A6. Triazolam is matabolized by CP450-3A4. Edward Zabawski, DO, R.Ph. -------------------- Would like to add saquinavir (Invirase TM) on your list, a protease inhibitor for HIV patients. Because of its poor bioavailability (4%), it is even recommended to be taken with two glasses of grapefruit juice. Hans J. Kammler -------------------- I too thought naringin and naringenin was inhibiting degradation of cyclosporin, but the following reference suggests that this is not the case, so the active ingredient in grapfruit juice reamins unidentified. I wonder what sorts of stuff patients are taking in their Health food" and "natural remedies" which could be interfering with their medications, or exacerbating certain disease processes. A "patient information brochure" with some of these "natural remedies" (or even with grapefruit) might frighten the daylights out of some patients. Title: Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Title Abreviation: Life Sci Date of Pub: 1996 Author: Edwards DJ; Bernier SM; Issue/Part/Supplement: 13 Volume Issue: Pagination: 1025-30 Abstract: The effect of various citrus juices and solutions of naringin on CYP3A activity in rat liver microsomes was compared by measuring the formation of 6 beta-hydroxytestosterone from testosterone. Control enzyme activity was reduced by more than 70% by grapefruit juice. Freshly-squeezed sour (Seville) orange juice containing 20% as much naringin was comparable to grapefruit juice in its ability to inhibit microsomal activity. An aqueous solution of naringin at the same concentration as in grapefruit juice produced only a small decrease in 6 beta-hydroxytestosterone formation. Dilution of grapefruit juice with a naringin solution reduced the inhibitory activity of the juice even though naringin concentration did not change. Naringenin did not form under the incubation conditions used indicating that it did not contribute to the inhibition produced by grapefruit juice. Finally, organic extracts of grapefruit juice possessed considerable inhibitory activity even though naringin was not extractable. These data suggest that grapefruit juice inhibits CYP3A activity in vitro and that neither naringin nor naringenin are primarily responsible for this effect. A compound present in both grapefruit juice and Seville orange juice and extractable into organic solvents appears to be responsible. Abstract By: Author Address: Department of Pharmacy Practice, College of Pharmacy & Allied Health Professions, Wayne State University, Detroit, Michigan, USA. Kevin Smith -------------------- Cyclosporine was a recent discussion topic for this list. Yesterday received the latest Mayo Clinic Proceedings - a great article Cyclosporine in the Treatment of Dermatologic Disease: An Update Mayo Clin Proc 1996;71:1182-1191 Reprint requests to: Dr. Pittelkow, Dept of Derm, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905 Robert M. Peppercorn, M.D. --------------------