Short therapeutical report Nonfluorinated corticosteroid topical preparations in children Nonjluorinated corticosteroid topical preparatio11S in children A. Kansky, B. Poclrumac and A. Godič SUMMARY Topical treatment of babies and little children with corticosteroids (CS) may provoke various side effects. Such a treatment should be carried out by experienced dermatologists or general practitioners educated in pediatric dermatology. In principle nonfluorinated preparations are advocated, as they cause less side effects than the fluorinated. A 10-year experience obtained with the alcloderm (Afloderm®) is discussed more in details. Introduction Corticosteroids (CS) applied topically in the form of ointments , creams, lotions, solutions or even applied intradermally seem to be an ideal drug for treatment of various inflammatory skin conditions. CS reduce or even completely suppress the symptoms of inflammation and alleviate accompanying symptoms such as pain, itching and paresthesia. CS inhibit the release of phospholipase 1, the enzyme responsible for liberation of arachidonic acid from phospholipids which are constituents of the celi membranes. As a consequence formation of pro- staglandin's (PG) and other derivatives of arachidonic pathway is inhibited. PG derive from arachidonic acid via the cyclooxigenase pathway, they contribute to the inflammation of the skin in contact allergic eczema, psoriasis and UV induced inflammation. They also enhance the itch induced by histamine. In addition the CS exhibit also antiproliferative and immunosuppressive effects. In view of such excellent therapeutic achie- vements a broad field of indications is open to the appli- Acta Dermatoven APA Vol 9, 2000, No 2 cation of CS in pediatric dermatology: seborrheic dermatitis , atopic dermatitis, various forms ofhereditary and acquired erythroderma, as well as further inflamma- tory conditions. Main characteristics oj corticosteroids The anti-inflammatory action of CS is on the mole- cular leve! stili not completely clarified. According to a simplified the01y free CS diffuse across the celi mem- brane and become bound to cytoplasmatic receptors which then become translocated into the nucleus. The hormone-receptor complex binds to a receptor site on one DNA strand associated with a particular gene, activa- ting transcription of that gene. The specific messenger RNA is then exported from the nucleus and translated to the ribosomes (1). The !atest investigations indicate however that the process is by far more complicated and 67 Nonjluorinated corticosteroid topical preparations in children that in addition to receptors various signal transducing and transcription molecules e.g. AP-1, NF- KB, 1-KBX are involved (2). Unfortunately CS, especially if administered not care- fully enough, may cause a number of side effects. The risk is greater when treating children, which fact necessi- tates that the therapeutist be familiar with the untoward effects. These are both local and systemic. Local side effects include development of skin atrophy, persistent erythema, teleangiectasia, papules and pustules, steroid acne , striae distensae, gluteal granulomas, hypertrichosis, pigmenta! changes and seldom a contact sensitization. A delayed healing of erosions and wounds may also be observed. Systemic side effects are Cushingoid appearance , dwarfism, dysbalance of electrolytes, steroid diabetes, increased catabolism of proteins, arterial hypertension and osteoporosis. Systemic Addisonian crisis (nausea, anorexia, postural hypotension, vascular collapse) has been reported with the use of topical CS. One bas to be especially careful when treating large or eroded surfaces with fluorinated CS in small children. Basic structure of CS consist of the 21 carbon-atom ring structure of sterols (Fig. 1). The activity of CS is dramatically enhanced by the introduction of an unsaturated bond between the first two carbon atoms, by the nature of the side chains, particularly on the 21 C position, and by fluorination of the 9a position. The first CS available for clinical use (cortisone) did not contain halogens. Halogenation of the basic steroid structure in the 9a position improves the activity, but also increases the side effects (3). For better penetration through the skin, a lipophilic component was added to CS, with the binding of a chemical group e .g. acetonide, valerate or propionate, and by the substitution of the hydroxyl group at the C 21 with chlorine. Nonfluorinated corticosteroids Pediatric dermatologists prefer to use nonfluorinated CS as they are less prane to provoke local or systemic side effects taking into account the long-term applica- tion. The majority of the little patients are referred to dermatologists because of chronic skin disorders: se- borrhea, atopic dermatitis, various erythemas, acquired and hereditary erythroderma, various eczemas, here- ditary bullous epidermolysis and others. Among the factors promoting the frequency and extent of side effects should be mentioned the follo- wing: magnitude of the treated area of the skin, inflamed o~ eroded surface, delicate skin of babies, intertriginous areas, scalp, scrotum and specially application of occlu- sive dressings (diaper area), but also addition ofkerato- lytics and quality of the vehicle. Compounds that contain 68 Short therapeutical report 21 !D 20 [fil 12 17 16 15 2 4 6 Figure 1. The configuration oj the basic corticosteroid structure. higher amounts of propylene glycol tend to be more patent. According to the potency of their action measu- red mainly as their vasoconstrictive effect, various CS may be assigned to one of the following classes: i) m.ildly patent, ii) moderately patent, iii) patent or iv) very patent (4) . Other authors recognize a classification into seven classes (5). These differences in the pharmaco- logical activities depend mainly on the chemical stru- cture and the concentration of CS, but also on the quality of vehicle. It is generally accepted that nonfluorinated CS cause fewer side effects than the fluorinated ones. The nonfluorinated CS are in principle less patent than the fluorinated and may be assigned to one of the first two above-mentioned classes. Hydrocortisone, predni- solone and alclometasone were among the first used for topical application in dermatology. Some of nonfluo- rinated CS are presented in Table 1. Clinical experience with alclometasone In principle all the nonfluorinated CS listed in Table 1 have certain advantages but also minor shortcomings. Experienced clinicians know that a balanced judgement concerning the efficiency and safety of a drug can be offered only after it had been in use for a number of years. This is the reason why we decided to make this short report on our experience with alclometasone dipropionate (Ajloderm® "J, which we have been using in pediatric dermatology for years. We started to use Afloderm® in our departrnent more than ten years ago. During the following years other nonfluorinated CS became available. We however stili use Afloderm® in our daily work with patients. In such a way we have been able to gather ample experience * Afloderm® Be\upo, Koprivnica, Croatia Acta Dermatoven APA Vol 9, 2000, No 2 Nonjluorinated corticosteroid topical preparations in children Short therapeutical report Table 1. Generic and proprietary names oj some topical nonfluorinated corticosteroids used in Slovenia Potency Generic names Mild alclometasone dipropionate Moderate hydrocortisone valerate hydrocortisone probutate mometazone furoate conceming the activity and safety of this drug. Afloderm® is available as a cream or ointment in various concentra- tions, which fact is important in choosing the appropri- ate preparation. Nonfluorinated CS are in principle safer compared to the fluorinated compounds, nonetheless one should be careful when using them in children, especially in babies, as their skin is not fully developed. When planning such a treatment a correct diagnosis should be made first, the stage of inflammation should be recorded (acute, sub-acute, chronic), and the appro- priate preparation chosen (cream, ointment). The pharmacodynamic characteristics, the mode of penetration into the skin (transepidermal or transfo- llicular) as well as the absorption of the preparation should also be considered. The amount of the drug absorbed depends on the quality of the skin and the specific area of the skin surface involved. The delicate skin of babies in general and specially in intertriginous areas Ceven in adults) is much more prone to absorption compared to the skin of palms or soles, where it is redu- ced. Further factors also enhance the penetration. Humi- dity has a similar effect as occlusive dressings. Hyper- emia of the skin, the number of hair follicles (scalp or pubic area) as well as the form ofthe preparation (emul- sion orgel) or the content propylene glycol also increase the absorption. All these guidelines have to be conside- red before applying the treatment with CS. The disorders in which we frequently use alclometa- sone are atopic dermatitis, allergic and irritant dermatitis as well as other acquired and hereditary skin infla- mmations. In the majority of our children erythema of the skin was observed; a skin infiltration, in some instan- ces scales and itch were expressed too. In most cases the cream or ointment was applied once daily, always without an occlusive dressing. In our initial experiences with Afloderm® the leve! of cortisol was assessed in plasma and the patients were carefully observed for the appearance of eventual side effects . At the end of the treatment with alclometasone we were able to confirm that we observed neither variation in plasma cortisol nor side effects on the skin. After more than 10 years ' lasting experience with Afloderm® we have basically observed no serious side 70 k Proprietary names Afloderm® cream, ointment Westcord® cream, ointment Pande!® Elocom® cream, ointment effects, like skin atrophy, striae or telangiectasias. Such manifestations were recorded only in a few patients with chronic illness whose parents chose on their own ini- tiative to use other CS preparations additionally to Afloderm® Conclusions At the end of our short experience-report on the use of nonfluorinated CS in pediatric dermatology we would like to draw the following conclusions: l. Nonfluorinated CS are definitely preferred to fluori- nated CS. 2. Before starting the treatment the diagnosis and the stage of the disease have to be specified. 3. The appropriate form of the preparation should be selected. 4. The application of CS shouldn't last too long. 5. The preparation should be applied two times a day only in the acute stages of the condition, during a few days only. 6. As a rule CS should be applied once daily and as soon as possible the treatment switched to preparations not containing CS. 7. In the cases where a longer lasting treatment is pla- nned the so-called alternating scheme is advocated: one-week nonfluorinated CS, one-week preparation not containing CS. 8. When treating chronic conditions the dilution of proprietary preparations with the pure base (Belobase®, Diprobase®, Linola® or other) and water should be con- sidered. The authors would like to thank Barbara j. Rutledge Jor reviewing the English. Acta Dermatoven APA Vol 9, 2000, No 2 NOJJfluorinated corticosteroid topical preparations in children Short t herapeutical report C E S l. Ebbling FJG. Functions of the skin. In: Rook A et al, Textbook of Dermatology, S'h ed, Champion et al eds, Blackwell, Oxford, 1992, 140-6. AUTHORS' ADDRESSES 72 2. Werth VP, Lazarus GS. Systemic Glucocorticoids. In: Fitzpatrick's Dermatology in General Medicine, S'h ed, Freedberg et al eds, McGraw Hill, New York,1999 , 1783-9 3. Bauman L,Kerdel F. Topical Glucocorticoids. In: Fitzpatrick's Dermatology in General Medicine,5'h ed, Freedberg et al eds, McGraw Hill, New York 1999; 2713-7. 4. Griffiths WAD, Wilkinson JD. Topical Therapy. Topical steroids. In: Rook A et al, Textbook of Dermatology,6'h ed, Champion RH et al eds, Blackwell, Oxford 1998, 3547-53. 5. Werth VP, Lazarus GS. Systemic Glucocorticoids. In: Fitzpatrick's Dermatology in General Medicine, 5'h ed, Freedberg et al eds, McGraw Hill, New York 1999; 278-9. Aleksei Kansky MD, PhD, professor oj dermatovenereology, Dpt. Dermatovenereology, University Medical Centre, Zaloška 2, 1525 Ljubljana, Slovenia. Božana Podrumac MD, dermatovenereologist, same address Aleksander Godič MD, MSc, resident, same address. Acta Dermatoven APA Vol 9, 2000, No 2