Case Report: In Situ Vaccination by Autologous CD16+ Dendritic Cells and Anti-PD-L 1 Antibody Synergized With Radiotherapy To Boost T Cells-Mediated Antitumor Efficacy In A Psoriatic Patient With Cutaneous Squamous Cell Carcinoma.

The combination of radiotherapy and immunotherapy improves the survival rate of patients with malignancies developed through escape from T-cell-mediated immune surveillance. Immune checkpoint inhibitors, such as anti-programmed cell death protein-ligand 1 (anti-PD-L1) antibody, are used to rescue exhausted T cells. Simultaneously, dendritic cells (DCs) which are antigen-presenting cells that can initiate T-cell activation, are used to induce a tumor-specific immune response. However, the synergistic antitumor efficacy of the aforementioned combinational immunotherapy with intratumoral injection of low-dose DCs has not been reported, and the underlying therapeutic mechanism requires further investigation. Herein, we present the special case of a psoriatic patient with cutaneous squamous cell carcinoma (cSCC) in the right inguinal region, these two diseases characterized by opposing contradiction, further complicating treatments and side-effect management efforts. To treat the intractable SCC without exaggerating psoriasis, we developed the triple-regimen therapy (TRT) with the intratumoral injection of low-dose autologous DCs and anti-PD-L1 combined with radiotherapy. The injected DCs were obtained simply through leukapheresis without prior G-CSF administration for mobilization nor tumor-antigen loading for expansion. The patient received three radiation doses (24, 18, and 18 Gy) combined with three intratumoral injections of anti-PD-L1 antibody (40, 60, and 120 mg) plus autologous DCs (80% of the DC subpopulation being CD16+ myeloid DC with approximate amounts of 7.3 × 104, 2.5 × 106, and 1.7 × 107) within 10 weeks. The efficacy of the TRT was encouraging in shrinking tumor mass with remarkable SUVmax reduction (approximately 42%) on FDG PET-Scan despite relatively low-dose DCs were available. The low-dose intratumoral immunotherapy induced mild cutaneous side effects as expected. The transcriptomes were compared between pre-TRT and post-TRT biopsies to analyze underlying mechanical pathways of the TRT protocol. Over 10 highly significantly enriched T-cell-related pathways (P <0.0001) were identified in post-TRT biopsies. In addition, the activation of both innate and adaptive immunity was significantly enriched in post-TRT peripheral blood samples. We develop the easily accessible TRT which produces both local anti-tumor T-cell responses and systemic antitumor immunity for treating cSCC patients, especially for those with autoimmune disease.

Optimal Management of Corticosteroids in Patients with Intracranial Malignancies.

OPINION STATEMENT: Corticosteroids have been essential in the management of brain tumor patients for decades, primarily for the treatment of peritumoral cerebral edema and its associated neurologic deficits. Dexamethasone is the drug of choice with standard practice being administration up to four times per day, however, because of its long biologic half-life and high potency, once or twice a day dosing is likely adequate in patients without elevated intracranial pressure. The length of corticosteroid treatment should be limited to the shortest period of time to minimize the risk of potential toxicities that can significantly affect quality of life, as well as to avoid a possible detrimental impact on survival in high-grade glioma patients and abrogation of the effect of immunotherapy. Agents such as bevacizumab should be considered in patients who are unable to wean completely off of steroids as well as those who have symptomatic edema and are on immunotherapy. Several other agents have been studied without much success. An increased understanding of the complex pathophysiology of peritumoral vasogenic edema is critically needed to discover new agents that are safer and more effective.

Long-term effects of the intratracheal administration of corticosteroids for the prevention of bronchopulmonary dysplasia: A meta-analysis.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the most common complications in premature infants. Since inflammation plays a crucial role in the pathogenesis of BPD, anti-inflammatory drugs, such as corticosteroids, have long been the focus of prevention research. In this meta-analysis, we aim to explore the long-term effects of the intratracheal administration of corticosteroids (IAC) in preventing BPD. METHODS: EMBASE, MEDLINE, the Cochrane Library, Web of Science, CINAHL, Clinicaltrials.gov, the ISRCTN registry, and gray literature were searched to identify randomized controlled trials (RCTs) that evaluated the long-term effects of IAC for the prevention of BPD in premature infants. RESULTS: Five RCTs (n = 1515) were eligible for further analysis. The meta-analysis revealed that the incidence of neurodevelopmental impairment (NDI) did not significantly differ between the IAC group and the control group (relative risk [RR] 0.9, 95% confidence interval [CI] 0.79 to 1.03, P = .14). There was no significant reduction in long-term mortality (RR, 1.13; 95% CI, 0.9 to 1.41; P = .3) or the incidence of rehospitalization (RR, 0.99; 95% CI, 0.89 to 1.09, P = .82). No significant differences were observed between the IAC group and the control group with regard to height, weight and head circumference at the age of 18 to 36 months of postmenstrual age (PMA) (mean difference [MD], 0.14; 95% CI, -0.26 to 0.54, P = .48). CONCLUSIONS: Our study suggests that IAC in preterm infants does not have significant long-term benefits or adverse outcomes. However, before routine use, well-designed studies and studies involving large sample sizes are needed to confirm the pharmacokinetics and long-term effects of IAC.

A Narrative Review on Anti-Tumor Necrosis Factor α Therapies in Inflammatory Bowel Disease During Pregnancy: Immunoglobulin Placental Translocation and its Impact.

INTRODUCTION: Inflammatory bowel disease activity is associated with adverse pregnancy outcomes. Anti-tumor necrosis factor α therapy is often required to treat flares and to maintain disease remission. However, there are concerns regarding treatment with these agents during pregnancy, as they actively cross the placental barrier. MATERIAL AND METHODS: Studies regarding anti-tumor necrosis factor α therapy during pregnancy were identified from PubMed from 1958 to January 2018. The reference lists of the selected studies were reviewed to identify complementary publications. RESULTS AND DISCUSSION: Anti-tumor necrosis factor α agents are efficient treatments for moderate-to-severe inflammatory bowel disease and may ensure remission during pregnancy. Although these drugs cross the placenta, they are considered safe for both the mother and the fetus. Furthermore, up-to-date guidelines support therapy continuation during pregnancy aiming for disease control. The same guidelines also consider stopping treatment during the third trimester to limit maternal-fetal drug transfer. However, data shows that this strategy does not completely prevent fetus exposure. In addition, stopping treatment incurs in risk of disease flare and threatens subsequent therapy response. Fetus drug exposure has not showed an association with adverse childhood development. However, as infant drug levels could be detected up to seven months after birth, postponement of live virus vaccination is recommended. CONCLUSION: There should be no disagreement among the medical community as to the need to maintain therapy aiming for disease remission during gestation in inflammatory bowel disease. Anti-tumor necrosis factor α agents are safe for both the mother and the fetus.

Introdução: O melhor preditor de complicações durante a gravidez, na doença inflamatória intestinal, é a atividade da doença. A terapêutica com agentes anti-tumor necrosis factor α atravessa a barreira placentária o que levanta questões relativamente à sua segurança durante a gravidez. Material e Métodos: Revisão bibliográfica suportada a partir de artigos indexados na PubMed (1958 a 01/2018) sobre a terapêutica anti-tumor necrosis factor α durante a gravidez na doença inflamatória intestinal. Resultados e Discussão: Os agentes anti-tumor necrosis factor α são eficazes na doença inflamatória intestinal e podem garantir a remissão clínica durante a gravidez. Estes fármacos atravessam a barreira placentária, mas são seguros para a mãe e feto. Neste sentido, as orientações atuais defendem a manutenção terapêutica durante a gravidez para assegurar a remissão clínica. Paralelamente, as mesmas orientações consideram a suspensão terapêutica durante o terceiro trimestre para limitar a exposição fetal ao fármaco. No entanto, esta estratégia não só não previne totalmente a exposição fetal, como aumenta o risco de agudização da doença e da perda de resposta à terapêutica após o seu reinício. Esta exposição fetal não está associada a alterações do desenvolvimento in utero ou neonatal. Ainda assim, uma vez que é possível dosear fármaco no recém-nascido até aos sete meses de vida, recomenda-se adiar a administração de vacinas vivas em recém-nascidos expostos. Conclusão: Não deve haver discordância na comunidade médica quanto à necessidade de garantir a remissão da doença inflamatória intestinal durante a gestação. Os agentes anti-tumor necrosis factor α devem ser vistos como opções terapêuticas seguras para mãe e feto durante a gravidez.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use. Thiopurines are the next step in the treatment of active UC but monotherapy during induction therapy in UC patients is not preferred because of their slow onset. Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-thioguanine nucleotide (6-TGN), has proven to be beneficial. Thiopurine S-methyltransferase (TMPT) plays a role in the metabolic conversion pathway of thiopurines and exhibits genetic polymorphism; however, the clinical benefit and relevance of TPMT genotyping is not well established. In patients with severely active UC refractory to corticosteroids, calcineurin inhibitors such as ciclosporin A (CsA) and tacrolimus are potential therapeutic options. These agents usually have a rather rapid onset of action. Monoclonal antibodies (anti-tumor necrosis factor [TNF] agents, vedolizumab) are the last pharmacotherapeutic option for UC patients before surgery becomes inevitable. Body weight, albumin status and antidrug antibodies contribute to the variability in the pharmacokinetics of anti-TNF agents. Additionally, the use of concomitant immunomodulators (thiopurines/methotrexate) lowers the rate of immunogenicity, and therefore the concomitant use of anti-TNF therapy with an immunomodulator may confer some advantage compared with monotherapy in certain patients. TDM of anti-TNF agents could be beneficial in patients with primary nonresponse and secondary loss of response. The potential benefit of applying TDM during vedolizumab treatment has yet to be determined.

Differences in Adverse Effect Profiles of Corticosteroids in Palliative Care Patients.

BACKGROUND:: Corticosteroids are frequently utilized in the palliative care setting to combat symptoms such as fatigue, dyspnea, pain, weakness, anorexia, cachexia, nausea, and vomiting. Often times, adverse effects arise with corticosteroid use, and it is unclear whether switching to another corticosteroid would reduce the risk of specific adverse effects or what measures can be taken to alleviate the adverse effects. OBJECTIVE:: This article aims to review the differentiating pharmacokinetics, potency, and adverse effect profiles of corticosteroids and summarize their clinical applicability. METHODS:: A literature review of "corticosteroids" and "palliative care" was performed using the PubMed database through July 2018. Original studies relevant to the purpose of this study were identified and those that met inclusion criteria were included. RESULTS:: Although corticosteroids share many common factors, including similar pharmacokinetic, pharmacodymanic, and adverse effect profiles, they have significant differences when the details of these variables are reviewed. Providers that prescribe corticosteroids for symptom management should be aware of these differences and the recommended management strategies. CONCLUSIONS:: Recognition of corticosteroid induced adverse effect profiles and possible management strategies is crucial to optimal symptom management in palliative care patients.

Injectable drug depot engineered to release multiple ophthalmic therapeutic agents with precise time profiles for postoperative treatment following ocular surgery.

A multi-drug delivery platform is developed to address current shortcomings of post-operative ocular drug delivery. The sustained biodegradable drug release system is composed of biodegradable polymeric microparticles (MPs) incorporated into a bulk biodegradable hydrogel made from triblock copolymers with poly(ethylene glycol) (PEG) center blocks and hydrophobic biodegradable polyester blocks such as poly(lactide-co-glycolide) (PLGA), Poly(lactic acid) (PLA), or Poly(lactide-co-caprolactone) (PLCL) blocks. This system is engineered to flow as a liquid solution at room temperature for facile injection into the eye and then quickly gel as it warms to physiological body temperatures (approximately 37 °C). The hydrogel acts as an ocular depot that can release three different drug molecules at programmed rates and times to provide optimal release of each species. In this manuscript, the hydrogel is configured to release a broad-spectrum antibiotic, a potent corticosteroid, and an ocular hypotensive, three ophthalmic therapeutic agents that are essential for post-operative management after ocular surgery, each drug released at its own timescale. The delivery platform is designed to mimic current topical application of postoperative ocular formulations, releasing the antibiotic for up to a week, and the corticosteroid and the ocular hypotensive agents for at least a month. Hydrophobic blocks, such as PLCL, were utilized to prolong the release duration of the biomolecules. This system also enables customization by being able to vary the initial drug loading to linearly tune the drug dose released, while maintaining a constant drug release profile over time. This minimally invasive biodegradable multi-drug delivery system is capable of replacing a complex ocular treatment regimen with a simple injection. Such a depot system has the potential to increase patient medication compliance and reduce both the immediate and late term complications following ophthalmic surgery. STATEMENT OF SIGNIFICANCE: After ocular surgery, patients routinely receive multiple medications including antibiotics, steroids and ocular hypotensives to ensure optimal surgical outcomes. The current standard of care for postoperative treatment after ocular surgery involves using eye drops daily, which has limited effectiveness mainly due to poor patient adherence. To improve patient experience and outcomes, this article presents the first thermoresponsive hydrogel able to release multiple drug molecules for the application of post-operative treatment following ocular surgery. By varying the parameters such as hydrogel type and polymer hydrophobicity, the drug release profile, duration and dosage can finely be tuned. The approach presented in this article can readily be applied to other applications by simply changing the drug loaded in the drug delivery system.

Antenatal corticosteroid treatment: factors other than lung maturation.

Antenatal corticosteroid (CS) therapy improves both fetal lung mechanism and gas exchange due to accelerated morphologic development of type one and two pneumocytes. This therapy also enhances the production of surfactant binding proteins and fetal lung antioxidant enzymes. In women with threatening preterm delivery, a single course is advocated between 24 and 34 weeks' gestation with either betamethasone (two doses of 12 mg 24 h apart) or dexamethasone (four doses of 6 mg at 12-h intervals). Such treatment reduces the rate of respiratory distress syndrome, comorbidity, and mortality in neonates in the first 48 h of life. The optimal time interval between CS administration and delivery is reported to be 1-7 days. Weekly repeat courses reduce the occurrences and severity of respiratory diseases but are associated with reduce fetal growth. Multiple courses should be avoided. However, a repeat course should be considered in women at risk of preterm birth 7 or more days after an initial course in women who remain at risk of preterm birth <34 weeks' gestation. CS may be harmful in growth restricted fetuses associated with an absent or reversed end-diastolic UA flow since they are at increased risk of acidosis and perinatal death. The purpose of this publication is to update and highlight antenatal CS therapy.

Corticosteroid-Sparing and Optimization of Mycophenolic Acid Exposure in Liver Transplant Recipients Receiving Mycophenolate Mofetil and Tacrolimus: A Randomized, Multicenter Study.

BACKGROUND: We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually. METHODS: Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant. RESULTS: One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P < 0.001) in arm A. CONCLUSIONS: Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence.

Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids.

The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time. The model adequateness was evaluated by various approaches including visual predictive check (VPC), prediction-corrected VPC, standardized VPC and normalized prediction distribution error. Covariates tested included age, body weight, height, body mass index, baseline FEV1, and sex. Age and height were found to have significant effects on the mean FEV1 level and no covariate was found to have an effect on the magnitude and timing of circadian rhythm. The model predicted that a minimum FEV1 occurred in the early morning and maximum FEV1 occurred in the early afternoon, with a population mean fluctuation of 170 mL, which is consistent with the finding that asthma symptoms usually exacerbate in the early morning for patients with persistent asthma. This developed model provides the first quantitative approach to describing FEV1 circadian rhythm with ICS background treatment and provided insight in designing future registration trials for asthma drug development.

Vigilância em Saúde da Criança: perspectiva de enfermeiros / Vigilancia en Salud Infantil: perspectiva de enfermeros / Child Health Surveillance: nurses perspective

RESUMOObjetivo:analisar concepções de enfermeiros sobre Vigilância em Saúde da Criança (VSC) em unidades de saúde da família.Métodos:estudo qualitativo, com análise temática dos dados, fundamentada no paradigma da Vigilância em Saúde. Foram realizadas entrevistas com 13 enfermeiros atuantes em município do interior paulista.Resultados:os enfermeiros conceberam VSC como acompanhamento ativo, integral, programado, identificando riscos/vulnerabilidades, por meio de ações multiprofissionais, intersetoriais e dependentes da participação materna. Constatou-se desenvolvimento parcial dessas premissas na prática, por dificuldades como falta de participação materna nas ações propostas, indisponibilidade de tempo para discussão e adoção de medidas nas unidades e desarticulação entre níveis e setores no município.Conclusão:é necessário maior investimento político e técnico para assegurar a adoção desse modelo nos diferentes setores e níveis de atenção do município.

RESUMENObjetivo:analizar las concepciones de los enfermeros en la vigilancia de la salud de los niños en las unidades de salud de la familia.Método:estudio cualitativo con el análisis temático de los datos, basado en el paradigma de la Vigilancia de la Salud. Se realizaron entrevistas con 13 enfermeras en la ciudad interior.Resultados:las enfermeras concibió la vigilancia de la salud del niño y la vigilancia activa, total, la identifi cación de riesgos/vulnerabilidades, a través de acciones multidisciplinario, intersectorial y dependiente de la participación materna. Encontramos lo desarrollo parcial de estos supuestos en la práctica, debido a las difi cultades, como la falta de participación de la madre en las acciones propuestas, la falta de tiempo para el debate y la adopción de medidas en las unidades y la falta de conexión entre los niveles y sectores en el condado.Conclusión:es necesaria una mayor inversión política y técnica para asegurar la adopción de este modelo en diferentes sectores y niveles de atención del municipio.

ABSTRACTObjective:to analyze conceptions of nurses on child health surveillance in family health units.Method:a qualitative study with thematic analysis of the data, based on the paradigm of Health Surveillance. Interviews were conducted with 13 nurses in a countryside city in the state of Sao Paulo.Results:nurses conceived child health surveillance as an active monitoring, which should be comprehensive, identifying risks/vulnerabilities, through multidisciplinary and intersectoral actions that are dependent on maternal involvement. We found partial development of these assumptions in practice, due to diffi culties such as lack of maternal involvement in the proposed actions, lack of time for discussion and adoption of measures in the units and disarticulation between levels and sectors of the city.Conclusion:a greater political and technical investment is needed to ensure the adoption of this model in different sectors and levels of care of the city.

Enhanced epidermal localization of topically applied steroids using SPACE™ peptide.

The balance of efficacy and safety of topical corticosteroids (TCs) depends on their ability to penetrate into and be retained within the skin. Here, we evaluated the ability of SPACE™ peptide to enhance epidermal delivery and localization of three model TCs. In vitro and in vivo skin penetration studies were performed to evaluate penetration of TCs into and across the skin in the presence of various formulations of SPACE™ peptide. Topical formulations of corticosterone containing free SPACE™ peptide produced significantly enhanced epidermal penetration and localization. Ratio of drug deposition in the skin and receiver (efficacy/safety, indicative of ratio of local to systemic uptake) exhibited higher values for SPACE™ peptide-based formulation as compared to aqueous and hydroethanolic solutions and Cortizone™ cream. Mass spectrometry analysis showed that SPACE™ peptide associates with corticosterone, which may explain its enhanced retention effect. SPACE™ peptide also enhanced dermal retention of two more TCs (hydrocortisone and triamcinolone acetonide) compared to the vehicle control. An in vivo study in mice further established the ability of SPACE™ peptide to enhance skin retention of hydrocortisone without producing elevated blood concentrations. These results show that SPACE™ peptide is an effective additive to the formulation for enhanced skin localization of topical steroids.

Autoimmune pancreatitis: updated concepts of a challenging diagnosis.

Autoimmune pancreatitis is a benign process characterized by inflammation and fibrosis. It is now known that cases of "autoimmune pancreatitis" actually consist of two distinct pathologic entities. Type 1 autoimmune pancreatitis is a manifestation of a systemic process, immunoglobulin G subclass 4 (IgG4)-related disease. IgG4-related disease can affect virtually every organ system in the body. Type 1 affects older patients and is characterized by an elevated serum IgG4 level and sites of extrapancreatic disease. Type 2 autoimmune pancreatitis is a disease process confined to the pancreas. It affects younger patients and is associated with inflammatory bowel disease. Type 2 is not associated with elevated IgG4 levels or extrapancreatic disease. Both subtypes can mimic malignancy, particularly pancreatic cancer. Awareness of the clinical and imaging features of the subtypes of autoimmune pancreatitis is important to avoid an incorrect diagnosis of malignancy.

Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhaler.

BACKGROUND AND OBJECTIVE: We assessed whether co-deposition of a long-acting ß2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells. METHODS: Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. RESULTS: The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 ± 0.20%) compared with the single fluticasone formulation (2.36 ± 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. CONCLUSIONS: Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects.

The therapeutic potential of intraocular depot steroid systems: developments aimed at prolonging duration of efficacy.

BACKGROUND: Corticosteroids play a major role in the treatment of many diseases of the posterior ocular segment. Systemically or topically administered steroids usually do not attain therapeutic concentrations in the retina, as they must first cross the blood-retina barrier. Intravitreal application is a useful alternative means of achieving therapeutic concentrations in the posterior segment but must be repeated every few weeks, because drugs given in this way have a short half-life. Intraocular sustained-release implants have been now developed in order to prolong the effect of intravitreal drugs and to lessen the need for repeated application. Macular edema is a typical indication for intravitreal steroid treatment. METHODS: Selective review of the literature. RESULTS: Various intravitreal corticosteroid implants have been evaluated in prospective, randomized clinical trials in recent years, and some have been approved for clinical use. Implants are either longer-acting and non-resorbable (fluocinolone acetonide implants) or shorter-acting and resorbable (dexamethasone implants). Major adverse effects of intravitreal corticosteroids include the induction or worsening of cataracts and elevated intraocular pressure. The likelihood of a complication varies from implant to implant and depends on the duration of action of the particular one used. CONCLUSION: Intravitreal corticosteroid implants are a new option in the treatment of diseases of the posterior ocular segment. Long-term results are not yet available. The optimal treatment for these diseases will need to be the focus of further clinical research.

Droplet aerodynamics, cellular uptake, and efficacy of a nebulizable corticosteroid nanosuspension are superior to a micronized dosage form.

Inhaled corticosteroids are considered to be an effective prophylactic against the morbid symptoms of several lung diseases, but scope remains for improvement in drug delivery technology to benefit bioavailability and treatment compliance. To ascertain whether dosage form might influence bioavailability, the emission characteristics and efficacy of a nanoparticulate budesonide formulation (Nanagel®) were compared with those of a proprietary micronized suspension (Pulmicort®) when delivered as a nebulized aerosol to human airway epithelial cells in a culture model. Having the visual appearance of a clear solution, Nanagel® was delivered by both jet and vibrating mesh nebulizers as an increased fine particle fraction and with a smaller mass median aerodynamic diameter (MMAD) compared to the micronized suspension. Quantitative high performance liquid chromatography (HPLC) analysis of cultured epithelia one hour after treatment with Nanagel® revealed a significantly greater cellular accumulation of budesonide when compared with Pulmicort® for an equivalent dose, a differential which persisted 24 and 48 h later. A quantitative in vitro assay measuring the activity of enzymes involved in superoxide production revealed that stressed HaCaT cells (a long-lived, spontaneously immortalized human keratinocyte line) treated with Nanagel® continued to show significantly greater attenuation of inflammatory response compared with Pulmicort®-treated cells 24 h after the application of an equivalent budesonide dose. The present in vitro findings suggest that formulation of inhalable drugs such as budesonide as aerosolized nanoparticulate, rather than microparticulate, suspensions can enhance bioavailability with concomitant improvements in efficacy.

Local and systemic safety of intranasal corticosteroids.

The safety and efficacy of intranasal corticosteroids (INCs) are well established for the management of allergic rhinitis, rhinosinusitis, and nasal polyps. As seen in numerous studies, INCs demonstrate markedly reduced systemic bioavailability compared with oral and even inhaled corticosteroids and have shown an excellent safety profile over 3 decades of use. Nonetheless, concerns remain among some prescribers and patients that these agents may reach the systemic circulation in sufficient concentration to produce adverse effects (AEs). Available evidence does not support these concerns. A review of the published literature indicates that the side effect profiles of INCs consist primarily of a low incidence of mostly mild and often transient local AEs, such as nasal irritation and epistaxis.The second-generation INC agents currently in use (mometasone furoate nasal spray, fluticasone propionate, ciclesonide, and fluticasone furoate) have favorable pharmacokinetic characteristics that further minimize systemic bioavailability (< 1%) compared with older INCs and compared with oral agents, thereby limiting the risk for systemic adverse events.

Evidence-based neonatal pharmacotherapy: postnatal corticosteroids.

Corticosteroids are used in the neonatal intensive care unit primarily to treat two conditions: bronchopulmonary dysplasia (BPD) and hypotension (cardiovascular insufficiency). Historically, high-dose dexamethasone was used for BPD, but its use was later associated with adverse neurodevelopmental outcomes and decreased substantially. Data from randomized controlled trials regarding efficacy and safety of lower-dose dexamethasone therapy are insufficient to recommend its use. Hydrocortisone may be an alternative to dexamethasone, but again data are insufficient to support use. Hydrocortisone therapy is increasingly used to treat hypotension in critically ill newborns; however, the outcomes of this therapy must be evaluated in randomized trials.

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma.

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.

[Clinical relevance of distal airway involvement in asthma]. / Importancia clínica de la afectación de la vía aérea pequeña en el asma.

Asthma continues to be a global health problem, despite advances in diagnostic techniques and treatment. The inflammatory nature of asthma is currently indisputable, as is the involvement of the entire respiratory tree, both the proximal and most distal airways, which has been demonstrated in multiple studies. The development of the therapeutic arsenal, with more potent drugs and improved inhalation devices, has allowed a certain control to be maintained over the inflammatory process, although the inability to reach the most distal points of the airways has posed a stumbling block that seems difficult to overcome. However, the available information on the real role of distal airway involvement in asthma remains very scarce. Physiopathological evidence shows that, in addition to the large airways, the small or distal airways (those with a diameter of less than 2 mm) substantially contribute to the severity of asthma. Several studies have shown that the inflammatory process seems to be more intense in this area. This finding has been related to nocturnal asthma and an increase in glucocorticoid receptor-beta-expressing cells, associated with corticosteroid-resistant asthma and fatal asthma. Equally, small airway involvement seems to be a highly important factor in asthma in the pediatric age group.