The topical corticosteroid classification called into question: towards a new approach.

Vasoconstrictor assay described in 1962 was an interesting assessment of potency of topical corticosteroids at the beginning of these new therapies, however knowledge and technology have evolved and the classification should follow. A topical corticosteroids with a strong vasoconstrictor effect, as determined by vasoconstrictor assay, has not necessary a strong anti-inflammatory effect. Therefore a specific classification adapted to the therapeutic target is needed to be more efficient and thus reduce side effects and corticophobia.

[Naming and classification of steroids and human stress ulcers. Articles of historic significance published by Hans Selye 70 years ago]. / A szteroidok elnevezése, felosztása és az emberi stresszfekélyek. Selye János 70 éve megjelent történelmi jelentoségu cikkei.

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

Corticosteroid hypersensitivity studies in a skin allergy clinic.

INTRODUCTION: Corticosteroids can cause hypersensitivity reactions, particularly delayed-type allergic reactions. A new classification system for testing hypersensitivity to corticosteroids distributes the drugs into 3 groups according to molecular structure; patients are classified according to whether they are allergic to agents in 1 or more of the groups. We aimed to describe the clinical characteristics of corticosteroid-allergic patients treated at our clinic and apply the new classification system to them; we also compared these patients' characteristics to those of others treated at our clinic. MATERIAL AND METHODS: Retrospective study of cases of delayed-type corticosteroid hypersensitivity treated in the skin allergy clinic of a tertiary level hospital over an 11-year period. RESULTS: We reviewed the records of 2857 patients, finding 33 with at least one positive patch test result showing corticosteroid hypersensitivity. Atopic dermatitis and hand involvement were less common in our corticosteroid-allergic patients. All were allergic to a group 1 corticosteroid (most often, budesonide, the culprit in 87.9%). Testing with a specific corticosteroid series revealed that 14 (42.4%) were also allergic to corticosteroids in group 2 and/or group 3. None were allergic exclusively to group 2 or group 3 agents. Twenty-one patients were exposed to a corticosteroid cream from a group their patch test results indicated allergy to; 13 of them (61.9%) did not develop a hypersensitivity reaction. CONCLUSIONS: The Spanish standard series only contains group 1 corticosteroids. In the interest of improving allergy management, we recommend testing with a specific corticosteroid series and a patient's own creams whenever patch testing with a standard series reveals a hypersensitivity reaction to corticosteroids.

HANS SELYE 70 YEARS LATER: STEROIDS, STRESS ULCERS & H. PYLORI.

Although Hans Selye is mostly known for his discovery & development of the stress concept, he also introduced the first physiologically sound, structure-activity classification of steroids that was also based on the chemical structure of steroids in 1943. He not only introduced the names of glucocorticoids & mineralocorticoids but discovered the anti- & pro-inflammatory properties, respectively, of these steroids in animal models. Furthermore, he not only described the first stress-induced gastric ulcers in rats (1936) & characterized the first human 'stress ulcers' during the air-raids in London during World War 11 (1943). Thus, Selye was a much more productive & creative scientist than it is generally considered.

New insights about delayed allergic hypersensitivity to corticosteroids.

Corticosteroids are among the most commonly used drugs, both topically and systemically. Although unexpected and paradoxical, allergic hypersensitivity to corticosteroids is a common finding, delayed-type reactions being much more frequently encountered than the immediate-type ones. With regard to cross-reactions between corticosteroids, based on patch-test results and molecular modelling, we were recently able to simplify the previous classification into 3 different groups, i.e., Group 1: the non-methylated, most often non-halogenated molecules (Group A, D2 and budesonide), which produce most of the allergic reactions; Group 2: the halogenated molecules with a C16/C17 cis ketal/diol structure (acetonide Group B); and Group 3: the halogenated and C16-methylated molecules (Group C and D1) that only rarely produce allergy.

Corticosteroid cross-reactivity: clinical and molecular modelling tools.

BACKGROUND: Corticosteroids have been classified into following four cross-reacting groups in function of their contact-allergenic properties: A, B, C and D, the last subdivided into D1 and D2. Recent data indicate that C(16)-methylated and nonmethylated molecules need to be distinguished, the latter selectively binding with arginine to form stable cyclic adducts and producing considerably more positive reactions than the former. This study compares molecular modelling and patch-test results to determine cross-reactivity patterns. METHODS: The patch-test results obtained with 66 corticosteroid molecules in 315 previously sensitized subjects were analysed and correlated with modelling and clustering in function of the electrostatic and steric fields of these molecules. RESULTS: The classification obtained after in silico hydrolysis of C(21) and C(17) esters was selected with an optimal cut into three clusters: the patients who reacted positively to cluster 2 (halogenated molecules from group B, with C(16)/C(17) cis ketal or diol structure) and cluster 3 (halogenated molecules from groups C and D1, C(16)-methylated) also reacted to cluster 1 (molecules mostly from groups A and D2, without C(16)-methyl substitution or halogenation and budesonide). The reverse, however, was not the case. CONCLUSION: Two patient profiles with probably different areas of immune recognition are identified as follows: the profile 1 patients were allergic to the frequently positively reacting cluster 1 only, for whom electrostatic fields (molecular charge) seem important; the profile 2 patients reacted to clusters 1 and 2 and/or 3, for whom steric fields (structure) are determinant and who probably presented a global recognition of the corticosteroid skeleton. A modified classification is thus proposed.

Immediate and delayed hypersensitivity to corticosteroids.

Corticosteroids are therapeutic agents used in cases of allergy and intolerance. Due to the antiinflammatory effects of the corticosteroids, hypersensitivity reactions often are considered to be a paradox. However, delayed-type reaction to corticosteroids is a frequent phenomenon in the daily routine. Non-responding eczema, development of subacute contact eczema, systemic contact dermatitis or maculopapular exanthemas can be a clinical symptom of a delayed-type hypersensitivity reaction to corticosteroids. Immediate-type hypersensitivity reactions to corticosteroids remain uncommon. Nevertheless, they can take a severe clinical course. Patients react with anaphylaxis after systemic administration or with aggravation of an allergic reaction under therapy with corticosteroids. Allergologic testing is necessary for diagnosis and providing alternative corticosteroids in case of an emergency.

COVID-19 and Corticosteroids: Unfamiliar but Potentially Fatal Infections That Can Arise following Short-Course Steroid Treatment.

Corticosteroid use is increasing worldwide as recent studies confer survival benefit of corticosteroids in the management of patients with severe COVID-19. Strongyloides and amebic infections are neglected diseases that can progress to catastrophic complications in patients exposed to corticosteroids, even with short treatment courses. To prevent lethal outcomes, clinicians should be aware of the threat these two parasitic infections pose to at-risk patients receiving corticosteroids, especially in the era of COVID-19.

Size and aggregation of corticosteroids used for epidural injections.

OBJECTIVE: The purpose of this study was to document particulate size in commonly used corticosteroid preparations. Inadvertent injection of particulate corticosteroids into a vertebral or foraminal artery can cause brain and spinal cord embolic infarcts and the size of the particles could be directly related to the chance that a clinically significant infarct would occur. One might assume that corticosteroids with particles significantly smaller than red blood cells might be safer. DESIGN: The following four types of corticosteroid preparations were used in various solutions and evaluated under light microscopy: dexamethasone sodium phosphate injection, triamcinolone acetonide injectable suspension, betamethasone sodium phosphate and betamethasone acetate injectable suspension, and methylprednisolone acetate injectable suspension. RESULTS: Dexamethasone sodium phosphate particle size was approximately 10 times smaller than red blood cells and the particles did not appear to aggregate; even mixed with 1% lidocaine HCl solution and with contrast dye, the size of the particles were unchanged. Triamcinolone acetonide and betamethasone sodium phosphate showed variable sizes; some particles were larger than red blood cells, and aggregation of particles was evident. Methylprednisolone acetate showed uniformity in size and the majority were smaller than red blood cells which were not aggregated, but the particles were densely packed. CONCLUSIONS: Compared with the particulate steroid solutions, dexamethasone sodium phosphate had particles that were significantly smaller than red blood cells, had the least tendency to aggregation, and had the lowest density. These characteristics should significantly reduce the risk of embolic infarcts or prevent them from occurring after intra-arterial injection. Until shown otherwise in clinical studies, interventionalists might consider using dexamethasone or another corticosteroid preparation with similar high solubility and negligible particle size when performing epidural injections.

Top 60 medications used for orofacial pain treatment.

This article introduces the 60 top pharmacologic treatments provided for chronic orofacial pain patients. It explains that the majority of "chronic" orofacial pain patients will not find a "cure" to their pain with medications but may find a way to manage their pain. The medications in this article are the most commonly utilized "pain" medications and where it exists. This article reviews some of the current evidence supporting their use on chronic orofacial pain disorders.

[Origin of corticosteroid glaucoma]. / Origine de la cortico-sensibilité.

Cortisonic glaucoma is frequent, clinically similar to chronic open angle glaucoma but directly linked to a corticosteroid treatment. Four risk factors are involved in the hypertonic effect of steroids: genetic ground: primary open angle glaucoma, diabetes, myopia, young age; intraocular penetrance and anti-inflammatory efficacy; the mode and duration of administration.

Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD.

Inhaled corticosteroids (ICSs) treatment combined with long-acting ß2-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia. There are indications that this association is stronger for fluticasone propionate than for budesonide. We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy. Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%-78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide. We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs. These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid.

A practical guide to dermatological drug use in pregnancy.

Although the developing fetus was once considered protected from the outside world, we now know that it can potentially be affected by any medication given to the mother. Despite this knowledge, use of medications during pregnancy is common and pregnant women often present for treatment of dermatological disease. Therapeutic options available for these patients will be discussed.

The degrees of UVB-induced erythema and pigmentation correlate linearly and are reduced in a parallel manner by topical anti-inflammatory agents.

To examine whether it is possible to evaluate the degree of ultraviolet B (UVB)-induced inflammation by measuring the degree of hyperpigmentation, we investigated the relationship between UVB-induced erythema and the subsequent pigmentation quantitatively. At 24 h and 7 d after irradiation with erythemogenic doses of UVB to the backs of 16 Japanese subjects, the degree of induced erythema (delta erythema index) and that of pigmentation (delta melanin index) were examined by an image analytic method using a videomicroscope interfaced with a computer. The relationship between two indices was linear in each subject, and the correlation coefficient was 0.83 when evaluated using whole data. The slope of the regression line for the delta melanin index against delta erythema index tended to become steeper as non-irradiated skin color became darker (r = 0.63), suggesting that more efficient melanogenesis takes place after the same level of inflammation in the subject with darker skin. Both erythema and hyperpigmentation were suppressed significantly and in a parallel manner by corticosteroids and indomethacin applied topically immediately after UVB irradiation. These results imply that the post-inflammatory hyperpigmentation correlates closely with the severity of the prior inflammation and that chemical mediators released in the inflammatory process have considerable influence on the melanogenesis. We conclude that the measurement of UVB-induced hyperpigmentation can be utilized for the assessment of topical anti-inflammatory agents, unless these have direct actions on the tyrosinase activity of melanocytes.

Recent advances in treatment strategies for atopic dermatitis.

A wide range of different therapeutic regimens are used for atopic dermatitis. Although many treatment modalities are well established worldwide among clinicians, only the minority of these therapy recommendations are based on results of randomised controlled trials (RCTs). To close the gap between such 'generally' recommended therapies and therapies that are based on data from controlled trials, this review focuses not only on the pharmacological and clinical aspects of the currently proven agents, but also on the advantages and disadvantages of therapies that have not yet been completely tested.A review of the available literature concerning the pharmacological profile and also the level of evidence of therapeutic efficacy of all currently known topical and systemic agents for the treatment of atopic dermatitis reveals a large gap between the knowledge concerning the pharmacological action in vitro and the evidence of clinical efficacy in many cases. We agree with the conclusion of previous reviews that numerous therapies for atopic dermatitis urgently require more independent RCTs and especially comparative trials (e.g. corticosteroids vs calcineurin inhibitors). These are required in order to facilitate the choice of therapeutic strategy for the individual treatment of atopic dermatitis, with its broad spectrum of clinical manifestations and potential complications in adult patients and, particularly, in children.Finally, we also review preclinical trials with several new drugs. Immunomodulators appear to promise a new dimension for the future of therapy for atopic dermatitis, especially for severe and otherwise refractory forms or as alternatives to corticosteroids, that is, to treat facial atopic eczema without the risk of adverse effects.

Topical corticosteroids and unwanted local effects. Improving the benefit/risk ratio.

The main goal of pharmacological research in the field of topical corticosteroids (TCs) is to dissociate efficacy and adverse effects as much as possible. The optimal use of TCs, i.e. the careful evaluation of the benefit/risk ratio, depends on: (i) the chemical structure of the TC; (ii) the type of vehicle; (iii) the mode of application; and (iv) the features of the skin to be treated. The recent availability of TCs characterised by a good dissociation between efficacy and adverse effects makes the classic and widely used classification system of TCs based upon potency out of date. Indeed, TCs with increasing potency have been characterised up to now, as a rule, by an increasing risk of adverse effects. Therefore, a classification system taking into major account the benefit/risk ratio seems particularly needed for clinical use in dermatology.

Skin reactions to inhaled corticosteroids.

Corticosteroids intended for inhalation into the lungs or into the nose have been used since the 1970s. Only 2 attempts to assess contact allergy attributable to inhaled corticosteroids in patients with asthma and/or rhinitis have been made, and only 1 single case of contact allergy attributable to budesonide and tixocortol pivalate was found. However, several case reports of allergic mucosal and skin symptoms caused by corticosteroids applied locally to the mucosa have been published. Local adverse effects from nasal corticosteroids have ranged from nasal congestion, pruritus, burning, and soreness to perforation of the nasal septum. Inhalation of corticosteroids into the lungs has been reported to cause pruritus, dryness, erythema and oedema of the mouth, a dry cough and odynophagia. Systemic signs reported from the use of nasal corticosteroids and inhalation of corticosteroids into the lungs have been eczematous lesions, particularly on the face, sometimes with spreading to the trunk and flexures. Urticaria has also been noted.

Studies in patients with corticosteroid contact allergy. Understanding cross-reactivity among different steroids.

BACKGROUND AND DESIGN: Most corticosteroid-allergic patients react to several corticosteroids. Irrefutable proof for the existence of cross-reactions is provided by reactions to substances to which the patient has never been exposed. Four groups of cross-reactions have been proposed, and our own observations support this. However, we have found that budesonide, in particular, tends to be involved not only in cross-reactions with corticosteroids of its own group (group B) but also with those of the ester group (group D). To test clinical observations on patients sensitive to corticosteroids and to establish a molecular basis for cross-reactivity patterns, a statistical analysis of our cases and a conformational study of major corticosteroids were performed. RESULTS: Statistically highly significant positive or negative correlations were found for the combination of tixocortol pivalate plus hydrocortisone and hydrocortisone plus budesonide, respectively. This indicates that budesonide and hydrocortisone or tixocortol pivalate detect different groups of corticosteroid-sensitive patients. Moreover, significant positive correlations were found between budesonide and amcinonide, both molecules belonging to the acetonide group C, and also between budesonide and some esters of group D such as hydrocortisone-17 butyrate and alclometasone dipropionate. These clinical observations were fully supported by a conformational analysis of the electronic shape of corticosteroids involved in this study. Groups A, B, and D were found to be highly homogeneous within each group in terms of molecular structures, while significant differences were observed among the groups. The special behavior of budesonide can be fully explained on the base of its unique molecular structure. Finally, molecular characteristics have been defined for each group. This could be useful for the prediction of potential cross-reactions to new corticosteroid molecules. CONCLUSIONS: The statistical analysis confirms that tixocortol pivalate and hydrocortisone contact allergies are definitely associated, while reactions to budesonide are strongly correlated with the reactions to both the acetonide group and the ester group. These clinical observations are fully supported by the conformational analysis of the molecules involved in this study. Tixocortol pivalate and budesonide should certainly be added to the standard series for the detection of patients sensitized to corticosteroids.