Corticosteroids.

Corticosteroids are commonly prescribed for a variety of indications due to the wide range of effects on the human body. Although they exhibit many therapeutic uses, corticosteroids are unfortunately known for their many dose- and duration-dependent toxicities. The purpose of this review is to explore indications for corticosteroid use, differences among formulations, and adverse effects and their management.

Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux.

There is concern that P-glycoprotein mediated efflux contributes to steroid resistance. Therefore, this study examined bidirectional corticosteroid transport and induction capabilities for P-glycoprotein (P-gp) to understand which of the systemic and inhaled corticosteroids interacted with P-gp to the greatest extent. Hydrocortisone, prednisolone, prednisone, methylprednisolone, and dexamethasone represented systemically active drugs, while fluticasone propionate, beclomethasone dipropionate, ciclesonide and budesonide represented inhaled corticosteroids. Aldosterone and fludrocortisone represented mineralocorticoids. All drugs were detected using individually optimised HPLC protocols. Transport studies were conducted through Caco-2 monolayers. Hydrocortisone and aldosterone had efflux ratios below 1.5, while prednisone showed a P-gp mediated efflux ratio of only 1.8 compared to its active drug, prednisolone, with an efflux ratio of 4.5. Dexamethasone and beclomethasone had efflux ratios of 2.1 and 3.3 respectively, while this increased to 5.1 for methylprednisolone. Fluticasone showed an efflux ratio of 2.3. Protein expression studies suggested that all of the inhaled corticosteroids were able to induce P-gp expression, from 1.6 to 2 times control levels. Most of the systemic corticosteroids had higher passive permeability (>20×10(-6) cm/s) compared to the inhaled corticosteroids (>5×10(-6) cm/s), except for budesonide, with permeability similar to the systemic corticosteroids. Inhaled corticosteroids are not transported by P-gp to the same extent as systemic corticosteroids. However, they are able to induce P-gp production. Thus, inhaled corticosteroids may have greater interactions with other P-gp substrates, but P-gp itself is less likely to influence resistance to the drugs.

Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. OBJECTIVES: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. METHODS: A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. RESULTS: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. CONCLUSIONS: Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

Unawareness and undertreatment of asthma: follow-up in a different geographic area in Denmark.

BACKGROUND: Early detection and treatment of asthma is important to minimize morbidity and healthcare costs. The objective of this study was to investigate asthma awareness and management in a western society. METHODS: In a random sample of 10 400 subjects aged 14-44 years, 686 (6.6%) reported symptoms of asthma in a standardized screening questionnaire. All 686 were evaluated by respiratory specialists and diagnosed by history, symptoms, lung function tests, bronchial challenges and allergy testing. Of these 686 participants, 69 (10%) had asthma alone, 205 (30%) had rhinitis alone and 217 (32%) had both asthma and rhinitis; 195 (28%) had nonasthmatic respiratory reports. RESULTS: Awareness of asthma was found among 163 (57%) of the 286 asthmatics, and 204 (95%) had doctor-diagnosed rhinitis as well. In a multivariate regression analysis, comorbidity with rhinitis (beta = 0.489, P < 0.001), smoking (beta = -0.116, P < 0.01), doctor-diagnosed bronchitis (beta = 0.086, P < 0.05), and earlier emergency visits at hospital (beta = 0.147, P < 0.001) was significantly associated with awareness. A difference in awareness was found between those who had asthma and rhinitis (62.2%) and those who had asthma alone (40.6%) (P < 0.01). Inhaled corticosteroids (ICS) were used by 27% of those with asthma, including 12% who used both ICS and long-acting beta-agonist. CONCLUSIONS: More than half of the persons with asthma were aware of their disorder; and the awareness was more likely in those with comorbidity of rhinitis. In general, asthma management was inadequate.

Patient and physician perspectives on the attributes of nasal allergy medications.

Allergic rhinitis (AR) often requires regular prophylactic use of allergy medications for the effective long-term management of nasal symptoms. However, patient adherence to AR treatment is frequently poor. The Allergies in America survey of nasal allergy sufferers assessed 2500 adults diagnosed with AR. Four hundred healthcare professionals also participated in this survey. Participants were interviewed about their perceptions of the effectiveness and tolerability of AR medications and the relationship of these parameters to patient satisfaction with therapy. Only 15% of nasal allergy sufferers reported that their intranasal corticosteroid (INCS) provided complete symptom relief, and 48% of patients indicated that their INCS did not provide 24-hour symptom relief. Healthcare professionals agreed that intranasal corticosteroids do not provide complete 24-hour symptom relief. The most commonly reported adverse effects of all nasal allergy medications were a drying feeling (47%), dripping down the throat (41%), drowsiness (37%), bad taste (32%), burning (17%), and headaches (16%). Many patients indicated that these adverse effects were moderately or extremely bothersome. Thirty-two percent and 25% of patients, respectively, discontinued treatment because their nasal allergy medications did not provide 24-hour symptom relief or were associated with bothersome adverse effects. Patients and healthcare professionals do not believe that INCSs provide complete 24-hour symptom relief. In general, allergy medications also are perceived as conferring unpleasant adverse effects. Lack of efficacy and bothersome adverse effects contribute to lack of satisfaction with treatment and treatment discontinuation in patients with AR.

Optimization of intranasal corticosteroid formulations for the treatment of allergic rhinitis.

Intranasal corticosteroids (INCSs) provide safe and effective treatment of allergic rhinitis (AR). Currently available INCSs differ in terms of the components included in each formulation that may influence efficacy, tolerability, and patient preference for treatment. Patient preference for a specific INCS is largely attributable to the sensory attributes that are dependent on characteristics of the formulation. Preservatives and additives can irritate and dry the mucosal membranes, or they can confer an unpleasant odor or taste to an INCS formulation. Spray volume also may affect patients' sensory perceptions of INCS formulations. Relative osmotic pressure or tonicity may affect nasal absorption and retention of an INCS and potentially affect clinical efficacy. A hypotonic suspension is a new formulation option for INCSs that may improve sensory attributes and has the potential to improve patient satisfaction and treatment outcomes in patients with AR. Optimization of INCS formulations may improve efficacy and tolerability and influence patient preference for treatment.

Intranasal corticosteroids in the treatment of allergic rhinitis.

Intranasal corticosteroids (INCSs) have been established as the first-line treatment of moderate to severe allergic rhinitis (AR). Compared with other monotherapies, INCSs are most effective at controlling underlying allergic inflammation and providing symptom relief. Although currently available INCSs show comparable efficacy in controlling nasal symptoms of AR, onset and duration of action are thought to be somewhat variable among the INCSs. The low frequency of side effects suggests that, at recommended doses, INCSs are safe for the treatment of AR. However, concerns remain regarding the long-term systemic side effects associated with INCS therapy. Recent clinical studies have indicated that ciclesonide provides effective relief from nasal symptoms of AR and may have a rapid onset of action. Moreover, the results of two clinical trials, including a 52-week study, have suggested that intranasal ciclesonide does not cause cortisol suppression. Furthermore, intranasal ciclesonide does not have an additive effect on the hypothalamic-pituitary-adrenal-axis function when administered in combination with inhaled corticosteroids (ICSs), indicating that intranasal ciclesonide can be used in combination with an ICS in patients with asthma and comorbid AR. Therefore, intranasal ciclesonide appears to provide an additional treatment option for patients with AR.

Access to inhaled corticosteroids is key to improving quality of care for asthma in developing countries.

Asthma is a worldwide public health problem affecting about 300 million people. The majority of persons living with asthma are in the developing world where there is limited access to essential drugs. The financial burden for persons living with asthma and their families, as well as for healthcare systems and governments, is very high. Inadequate treatment and the high cost of medications leads to disability, absenteeism and poverty. Despite the existence of effective asthma medications and international guidelines, and progress made in the implementation of such guidelines over the last decade, the high cost of essential asthma medications remains a major obstacle for patient access to treatment in developing countries. The International Union Against Tuberculosis and Lung Disease has evaluated this problem and created an Asthma Drug Facility (ADF) so that countries can purchase affordable, good quality essential drugs for asthma. The ADF uses pooled procurement along with other purchasing and supply strategies to obtain the lowest possible prices. Accompanied by the implementation of standardized asthma management, the increased affordability of drugs provided by the ADF should bring rapid and significant health and cost benefits for patients, their communities and governments.

Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism.

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 mug/kg per hour for 10 hours followed by 0.9 mug/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7+/-4.9 to 9.4+/-7.1 pg/mL; F=4.94; P=0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7+/-7.5 and 15.2+/-9.4 mm Hg during placebo and spironolactone, respectively; P<0.001 for angiotensin II) and decreased renal plasma flow (-202+/-73 and -167+/-112 mL/min/1.73 kg/m(2); P<0.001 for angiotensin II effect) similarly during placebo and spironolactone. Spironolactone enhanced the aldosterone response to angiotensin II (increase of 17.0+/-10.6 versus 9.0+/-5.7 ng/dL; P=0.002). Angiotensin II transiently increased free plasma F(2)-isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8+/-1.1 to 2.4+/-1.4 pg/mL; F=4.5; P=0.04) but spironolactone prevented this effect (F=6.4; P=0.03 for spironolactone effect). Norepinephrine increased blood pressure and F(2)-isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor-dependent mechanism in humans. In contrast, angiotensin II-induced oxidative stress, as measured by F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

Asthma inhalers and subsurface enamel demineralisation: an in situ pilot study.

AIM: The purpose of this pilot study was to identify the subsurface enamel demineralising potential of two possible acidogenic lactose-based powders and their corresponding generic pump inhalers. METHODS: Ten healthy non-asthmatic adults participated in a 5- leg randomised crossover study including a 10% sucrose control. A twice-daily 400 microg dose of inhaler was applied in vitro to a demineralised enamel slab on the buccal flange of a mandibular removable appliance before in situ placement for 14 days each. Lesion parameters were determined using transverse microradiography and digitised image analysis. RESULTS: Minimal demineralisation occurred with sucrose, both pump and one powder inhaler. The remaining powder was associated with remineralisation (p = 0.29). Overall, mean lesion depth increased (p = 0.12). CONCLUSION: Asthma inhalers failed to demonstrate a significant acidogenic/cariogenic effect.

Exaled nitric oxide and air trapping correlation in asthmatic children.

Exhaled nitric oxide (eNO) levels have been shown to correlate with atopy and with airway hyperresponsiveness but not with standard spirometry. The aim of our study was to evaluate the correlation between eNo levels and functional residual capacity (FRC), residual volume (RV), RV to total lung capacity (TLC) ratio, and pulmonary resistances in asthmatic children ages 6-13 years. Forty-nine patients (35 males) were enrolled in the study. Nineteen of them were not receiving inhaled corticosteroids. The eNO levels were measured by chemiluminescence's analyzer and lung function study were performed by body box plethysmography. As expected, there was no correlation between eNO levels and forced vital capacity (FVC); forced expiratory volume in the first second (FEV1); mid respiratory flow between 25 and 75% of the vital capacity (MEF(25 -75)), FEV1/FVC, and pulmonary resistances. Instead a correlation was found between eNO level and RV both considering all the study population together (r = 0.51, P = 0.001) and separately the asthmatic children not receiving ICS (r = 0.6, P = 0.003). In the patients receiving ICS the correlation was still present (r = 0.43, P = 0.01). The correlation between eNo levels and RV may reflect the effect of airway inflammation on NO production and diffusion as well as peripheral airway trapping and consequent RV.

Effect of steroids in combination with LH-RH on the release of LH and FSH in LH-RH-primed immature male rat.

LH and FSH release of immature male rats was remarkedably enhanced by LH-RH if primed with LH-RH one hour before. The effect of exogenous steroids on the action of the second LH-RH was investigated. C-18, C-19 and C-21 steroids in different doses were tested. Blood samples were collected from the jugular vein immediately before and 30 min after the second LH-RH injection. Serum LH and FSH were determined by respective radioimmunoassays. The concomitant increase of LH and FSH was not induced by all the steroids administered iv. Estrone or 17alpha-hydroxyprogesterone suppressed LH and FSH release. Estradiol-17beta preferentially suppressed LH release. Cortisone, progesterone or dehydroepiandrosterone significantly facilitated FSH release, whiel 20alpha-dihydroprogesterone or 20beta-dihydroprogesterone selectively promoted LH release. The sc injection of most steroids dissolved in oil tended to augment the acute release of LH but not FSH. 20alpha-Dihydroprogesterone was particularly potent in this concern. Dehydroepiandrosterone or androstenedione was effective in maintaining FSH release for a longer period. These data revealed that potentiated LH and FSH release induced by the second LH-RH was readily modified by steroids administered simultaneously.