The 70th anniversary of glucocorticoids in rheumatic diseases: the second youth of an old friend.

Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit-risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low-dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations.

[The history of the Science of Stress: From Hans Selye to the discovery of anti-inflammatory medication]. / L'histoire de la science du stress : de Hans Selye à la découverte des anti-inflammatoires.

To make an important scientific discovery that will make history takes a lot of determination, creativity, perseverance and luck! The story behind the discovery of stress and its biological basis is a fascinating one that places Dr. Hans Selye in the forefront. Dr. Selye was a great scientist that taught at the Université de Montréal from 1945 to his death in 1982. Dr. Selye was curious and hard working. He was determined to understand how various disorders can lead to similar physical manifestations, and this interest led him to discover the role of the adrenal glands involved in the stress response and to better understand the effects of glucocorticoids on the body. Today, the science of stress is based on the foundations established by Dr. Selye. In celebration of the 50th anniversary of the Département de psychiatrie de l'Université de Montréal, and the special issue of the Revue Santé Mentale au Québec, this historical review summarizes the discoveries of this great scientist who worked in Quebec.

[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.

[Steroids: The physiologic and pharmacologic effects of glucocorticoids]. / Szteroidok: A glükokortikoidok élettani és gyógyszertani hatásai.

Glucocorticoids are widely used in medical practice mainly for suppression of the immune system. According to Selye - who named them - the endogenous molecules are very important for the adaptation to challenges, stress. They were synthesized in the 1940s. Since then numerous data have been published about their production (also locally in several organs), transportation (primarily cortisol-binding globulin) and receptors (nuclear and non-genomic effects). Although glucocorticoids are primarily under the control of the hypothalamo-pituitary-adrenocortical axis, several other molecules (especially catecholamines) may also increase their secretion. Their permissive influences are dominant, thereby they are indispensable for the effect of numerous other molecules. Thus, glucocorticoids have very diverse influence from metabolism through cardiovascular effect to bone-metabolism, affecting even the central nervous system. They are also important in metabolic syndrome. Their extensive therapeutic usage are limited by side-effects, which could be diminished - among others - with concomitant usage of the anabolic dehydroepiandrosterone.

Equipoise in Research and the Development of Neonatal Interventions for the Management of Respiratory Distress Syndrome: A Historical Perspective.

The historical review of how evidence was developed for the management of respiratory distress syndrome in premature infants has not been clearly characterized. Knowledge of this process is essential to understand the role of equipoise and its influence on the decision to evaluate interventions as they were implemented in the practice of medicine. We suspect that errant approaches to clinical equipoise secondary to states of false certainty and false uncertainty have been important barriers to the timely acquisition and implementation of evidence-based knowledge necessary to improve outcomes in this fragile population of infants. When confronted with the decision to test an intervention, physicians should question whether they have lost clinical equipoise based on opinion, expertise, or observational data rather than evidence obtained from methodological inquiry; doing so facilitates reaching clinical equipoise and promotes the application of scientific methodology to answer relevant clinical questions. Timely acquisition of evidence-based knowledge can be viewed as an ethical imperative when the status quo may have negative consequences on outcomes for generations.

Glucocorticoids.

Glucocorticoids are the most effective anti-inflammatory treatment for allergic diseases, and inhaled glucocorticoids have now become the first-line treatment for asthma. Glucocorticoids were discovered in the 1940s as extracts of the adrenal cortex and this was followed by the isolation of adrenocorticotropic hormone (ACTH) from pituitary gland extracts. Cortisone and ACTH were found to be very beneficial in the treatment of rheumatoid arthritis and Kendall, Reichstein and Hench received the Nobel Prize in Physiology and Medicine for this work in 1950. Bordley and colleagues first showed that ACTH was very beneficial in the treatment of allergic diseases in 1949, but the use of systemic glucocorticoids was limited by side effects. Inhaled glucocorticoids were discovered from topical steroids developed for skin inflammation and beclomethasone dipropionate was introduced in 1972, initially in low doses but later in higher doses, and became the standard treatment for persistent asthma. Subsequently, inhaled glucocorticoids were combined with long-acting ß2-agonists in combination inhalers for even greater therapeutic benefit. There is now a good understanding of the molecular basis for the anti-inflammatory effects of glucocorticoids in allergic diseases. The search for even safer glucocorticoids based on the dissociation of anti-inflammatory and side effect mechanisms is currently ongoing.

Intranasal glucocorticosteroids - not only in allergic rhinitis In the 40th anniversary of intranasal glucocorticosteroids' introduction.

It has been 40 years since Niels Mygind's publication in British Medical Journal on intranasal application of beclomethasone dipropionate aerosol in allergic rhinitis (AR). Since then a new era in treatment of allergic and nonallergic upper airway diseases began. This publication presents current concepts on application of intranasal glucocorticosteroids (inGCS) in treatment of upper airway diseases and in particular of AR and rhinosinusitis. Nonquestionable advantage of inGCS is their strong anti-inflammatory local action with little impact on general health responsible for few and benign side effects. Main way of action of glucocorticosteroids is connected with binding to the intracellular glucocorticosteroid receptor and its impact on nuclear cytoplasmic transcriptional factors. Glucocorticosteroids suppress gene expression of factors responsible for generating and supporting inflammatory processes, proinflammatory cytokines and chemokines production, and adhesive molecules expression. It appears that glucocorticosteroids have also other mechanisms of action, non-involving intracellular receptors, leading to inhibition of early and late phase of allergic reaction. At the moment the following glucocorticosteroids are registered in Poland: beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, and mometasone furoate. Furoates earn special attention as their lateral furoate ester chain makes the molecules highly lipophilic, and hence easily absorbed by nasal mucous membranes, epithelium and cell membrane phospholipids. This minimizes their general action and maximizes local action. According to current state of knowledge topical glucocorticosteroids are used in the following upper airway diseases with different inflammatory mechanisms: AR, non-AR, particularly NARES, acute rhinosinusitis, chronic rhinosinusitis with and without nasal polyps, adenoid hypertrophy and rhinitis in bronchial asthma.

The COBRA trial 20 years later.

This article provides a perspective on the immediate and follow-up results of the COBRA trial that compared the combination of step-down prednisolone, methotrexate and sulfasalazine with sulfasalazine monotherapy in early rheumatoid arthritis (RA). The combination provided immediate relief of symptoms and signs of RA, but the clinical benefit compared to monotherapy appeared mostly dependent on low-dose glucocorticoid therapy that was mandatorily discontinued after 28 weeks. Strong benefit was apparent in the slowing of joint damage progression, and this effect persisted for over 10 years despite uncontrolled therapy after the trial period. In the trial toxicity of COBRA was less than monotherapy, and long-term safety of the regimen was comparable to regimens that do not include glucocorticoids. COBRA was the first study to validate the 'reverse-pyramid' concept in RA, and helped to establish the idea of a window of opportunity where the prognosis of RA may be altered with early and intensive therapy. Subsequent studies have shown COBRA is feasible in practice, acceptable to patients, and has efficacy similar to the combination of TNF inhibition and high-dose methotrexate, at a fraction of the cost.

The origins, results and consequences of the 1995 Arthritis Research Campaign Low-Dose Glucocorticoid Study.

The discovery and subsequent therapeutic use of glucocorticoids, which took 30 years, was stimulated by clinical observation and achieved by persistent investigation. Early reports of the potential of glucocorticoids to modify the underlying course of rheumatoid arthritis (RA) were overshadowed by pharmaceutical innovations with symptom relieving non-steroidal anti-inflammatory drugs (NSAIDs), and it was not until 1995 that clear-cut evidence of a powerful glucocorticoid disease-modifying action was published as the Arthritis Research Campaign Low-dose Glucocorticoid Study. This review reports how the study came to be designed and implemented, adds some additional information from the study not previously published, and considers the subsequent impact of the 1995 paper. Eighty years after Hench and colleagues made their first suggestion of benefit the UK National Health Service suggested all patients newly diagnosed with RA should have early access to glucocorticoid treatment.

Vasculitides throughout history and their clinical treatment today.

Therapeutic management of the vasculitides is closely linked to modern rheumatologic advances, particularly as it relates to the discovery and first clinical use of glucocorticoids. These compounds were introduced in the late-1940s for the treatment of rheumatoid arthritis, but soon after, clinicians in Europe and the United States realized that they could have a significant positive impact in systemic vasculitides. However, once it was realized that glucocorticoid use was associated with a high degree of morbidity, the search for better immunosuppressive agents with similar efficacy but improved safety profiles was on. During the past several years, several agents have been utilized for the therapeutic management of systemic vasculitides, and the list keeps growing with the development of newer compounds that have retained efficacy but with a better safety profile.

Recent progress in facial paralysis: advances and obstacles.

PURPOSE OF REVIEW: Facial paralysis is a devastating and debilitating condition for which a range of management options exists; all of them continue to have limitations. We review the recent scientific literature and highlight key developments and opportunities for further exploration with the goal that this may help direct clinical practice and research endeavor. RECENT FINDINGS: We reviewed recent findings in the evaluation of facial paralysis, pharmacological management, nerve injury prevention and treatment. This includes review of novel techniques using photography and videography. Review of surgical and adjunctive techniques identifies several refinements of existing techniques, some novel techniques, and the value of adjunctive materials and therapies. SUMMARY: Management of facial paralysis remains an area of active investigation and innovation. The challenge to researchers and care providers will be to continue to explore and refine management strategies while maintaining rigorous and standardized means of evaluation and follow-up, such that outcomes may be determined and reported accurately and in a way that they can be transferred to other clinical practices. Further study of the role of growth factors and stem cells in facial nerve regeneration is critical, and is the most likely means of surmounting the remaining barriers to successful outcomes in alleviating the ravages of this devastating malady.

Conference summary and conclusions. A comprehensive approach to predicting and managing mood effects of glucocorticoids.

The discovery of glucocorticoids and their enormous therapeutic benefits led to the use of these compounds as valuable medications for a wide variety of diseases. In 1950 this effort was ushered in by a landmark event-the awarding of the 1950 Nobel Prize in Physiology and Medicine to Drs. Phillip Hench, Edward Kendall, and Tadeus Reichstein. It was Hench who described and researched the successful use of the glucocorticoid, cortisone, and pituitary adrenocorticotrophic hormones to treat rheumatoid arthritis. Significant scientific discovery preceded Hench and colleagues' efforts, but the revolutionary accumulation of discovery in glucocorticoids since then is one of the unique scientific stories in the history of medicine. The scientific conference upon which this volume is based represents an attempt to convene a state-of-the-science meeting on the current understanding and scientific status of this fascinating, far-reaching, and fast-moving field. This last chapter will summarize the exciting presentations of this 2-day conference.

[Sympathetic ophthalmia, enigmatic malady]. / Ophtalmie sympathique, maladie énigmatique.

Sympathetic ophthalmia was a well-known but greatly feared entity in the 19th and most of the 20th century. This article reviews the Canadian medical literature, tracing the prophylactic and therapeutic modalities offered to treat this blinding affliction.

The role of glucocorticoids in secretory activation and milk secretion, a historical perspective.

In this review we present our current understanding of the role of glucocorticoids in secretory activation and milk secretion by looking at the literature from a historical perspective. We begin with the early endocrine ablation experiments and continue from there to show that glucocorticoids are not just necessary for secretory activation and milk secretion--but mandatory. Specifically, we discuss the importance of glucocorticoids to: (1) induce the formation of ultrastructural components necessary to support milk synthesis and secretion, including rough endoplasmic reticulum and tight junction sealing; (2) regulate milk protein gene expression; and (3) prevent the second phase of involution, possibly by preventing the breakdown of the extracellular matrix.

A history of adjunctive glucocorticoid treatment for pediatric sepsis: moving beyond steroid pulp fiction toward evidence-based medicine.

OBJECTIVES: To review the history of clinical use of corticosteroids with particular reference to adjunctive therapy for severe pediatric sepsis and, in this context, to provide an overview of what is known, what is not known, and what research questions are particularly relevant at this time. DATA SOURCE: Literature review using PubMed, cross-referenced article citations, and the Internet. CONCLUSIONS: The history of corticosteroid use in clinical medicine has been colorful, noisy, and always controversial. Therapeutic corticosteroid indications that initially seemed rational have frequently been refuted on closer, rigorous clinical trial inspection. Although it may be prudent to provide stress-dose steroids to children with septic shock who are clinically at risk for adrenal insufficiency (chronic or recent steroid use, purpura fulminans, etomidate or ketoconazole administration, hypothalamic, pituitary, adrenal disease), the safety and efficacy of stress-dose steroids as general adjunctive therapy for pediatric septic shock have not been established. Glucocorticoid administration does add potential risk to critically ill children. In particular, although adjunctive corticosteroids may hasten resolution of unstable hemodynamics in septic shock, this may occur at the metabolic cost of hyperglycemia. Clinical practice that fosters innovative therapy (off-label use) over research probably represents bad medical and social policy. Accordingly, pediatric critical care researchers have a responsibility to generate pediatric-specific evidence-based medicine for adjunctive corticosteroid therapy for severe sepsis in children.

A brief history of inhaled asthma therapy over the last fifty years.

This year is the 50th anniversary of the introduction into clinical use of the first modern inhaler for the management of asthma--the pressurised metered-dose inhaler (pMDI). The pMDI was initially used for the administration of the non-selective beta-agonists adrenaline and isoprenaline. However, the epidemic of asthma deaths which occurred in the 1960s led to these drugs being superseded by the selective short-acting beta-agonist salbutamol, and the first inhaled corticosteroid (ICS) beclomethasone. At the same time, sodium cromoglycate was introduced, to be administered via the first dry-powder inhaler--the Spinhaler--but owing to its relatively weak anti-inflammatory action its use is now very limited. Over the last 10 years, the long-acting beta-agonists (LABAs) have become an important add-on therapy for the management of asthma, and they are now often used with ICS in a single ICS/LABA combination inhaler.

Treatment of acute lung injury: historical perspective and potential future therapies.

The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.