Soft Drugs 18. Oral and Rectal Delivery of Loteprednol Etabonate,a Novel Soft Corticosteroid,in Rats—for Safer Treatment of Gastrointestinal Inflammation

Purpose. As a safe anti-inflammatory corticosteroid, the utility of loteprednol etabonate (LE) for the treatment of gastrointestinal inflammation, via oral and rectal administration, was investigated in rats. Methods. In vivo, LE solution and suspension were orally administered (20 mg/kg), and various LE preparations (solution, suspension & suppository) were applied in rectal loops (0.2 mg per loop). In vitro, various GI tissues were used to study the stability and partition of LE. Results. After oral administration of LE solution, LE reached the upper GI tract effectively, but not the colon, due to absorption and/or decomposition. In suspension, LE reached most of the GI tract (except rectum) in 8 hr and showed little absorption. After rectal applications, LE remained intact in the rectal loop for more than five hours with a slow rate of disappearance, however, LE distributed in the rectal membrane to some extent. The concentrations of LE and its inactive metabolites in plasma after both oral and rectal administrations were lower than the detection limit (0.1 µg/ml) at anytime during the experiments. In vitro, LE in solution was stable in stomach, but not in cecum, due to the hydrolysis by the cecal resident micro flora. In solution, LE distributed into the mucosal membranes efficiently (about 2.5 ~ 4.0 µg/g tissue). Conclusions. The results suggest that LE can be orally or rectally delivered in the GI tract for the topical treatment of the inflammatory bowel disease.     

Successful treatment of Rosai–Dorfman disease with low-dose oral corticosteroid

We present herein a Japanese case of Rosai–Dorfman disease (RDD) in which cutaneous manifestations completely remitted after treatment with low-dose oral corticosteroid. A 69-year-old Japanese man presented with a 1-year history of enlarged submandibular lymph nodes and subsequent nasal and pharyngeal bleeding. RDD was diagnosed based on biopsy results from a lymph node in the left parotid region. The patient had also noted several skin eruptions that repeatedly appeared and disappeared on the face and arms. Biopsies were taken from skin eruptions on the face and cuboidal fossa. Both biopsy specimens showed dense, well-demarcated infiltration of histiocytes, lymphocytes and multinucleated giant cells from just under the epidermis to the subcutaneous tissue. These histiocytes were positive for CD68 and S-100, but negative for CD1a, and some displayed emperipolesis. Given the histopathological findings and the fact that the patient was suffering from RDD, skin lesions were diagnosed as cutaneous manifestations of RDD. Cutaneous lesions gradually began to persist concomitant with enlargement of extranodal lymphadenopathy in the nasopharyngeal area. Increasing respiratory obstruction prompted a trial with oral prednisolone commencing at 0.4 mg/kg per day. Both the lymphadenopathy and skin lesions responded quickly. Within 3 months, all his skin lesions disappeared completely with almost complete resolution of lymphadenopathy. Twelve months after the beginning of oral prednisolone therapy, slight recurrence of mucosal and cutaneous lesions appeared, but disappeared quickly with an increase in prednisolone to 0.3 mg/kg per day. Low-dose prednisolone appeared very effective in the case of RDD.     

Prophylactic corticosteroid use prevents engraftment syndrome in patients after autologous stem cell transplantation

Engraftment syndrome (ES) following autologous stem cell transplantation (ASCT) at the time of neutrophil recovery may comprise fever, rash, pulmonary edema, or diarrhea. Usually, ES is easily manageable using corticosteroids but may prolong hospitalization. In two consecutive cohorts of subsequent patients with myeloma, lymphomas, and testicular/germ cell cancer, we assessed the benefit of corticosteroid use to prevent incidence and severity of ES following ASCT. Whereas Cohort A (82 patients) received no prophylactic corticosteroids, corticosteroids (4 mg dexamethasone oral daily) were started in Cohort B (60 patients) at day +9 until day +13 following ASCT. Steroid prophylaxis significantly reduced the incidence of ES (6/60; 10% vs. 33/82; 40%; p < 0.001). Hospitalization duration was longer in patients with ES than in patients without ES within both cohorts (in Cohort A: p = 0.007; and B: p = 0.011), but did not differ significantly between cohorts A and B. Finally, in Cohort A, there was a trend to an inferior 2‐year overall survival rate in patients without ES compared to patients with ES (p = 0.067), but definite conclusions are not yet allowed. Our results suggest that corticosteroid prophylaxis from days +9 to +13 following ASCT significantly reduces the risk of ES and shortens hospitalization duration.     

Ultrasound guided injection of recalcitrant plantar fasciitis

OBJECTIVE—To determine the effect of ultrasound guided injection in recalcitrant idiopathic plantar fasciitis.
METHODS—Four patients with a clinical diagnosis of idiopathic plantar fasciitis, who were unresponsive to palpation guided injection with triamcinolone acetonide and local anaesthetic, underwent ultrasonographic examination of the heel.
RESULTS—The following ultrasonographic features were noted:- (a) increased thickness of plantar fascia in symptomatic heels compared with asymptomatic heels, (b) loss of distinction of the distal plantar fascia borders, (c) reduced echogenicity of the plantar fascia. Ultrasound guided injection of the enlarged, hypoechoic plantar fascia resulted in complete relief in four of five heels(mean duration of follow up=24 months) in three cases. One patient developed a recurrence of symptoms after six months.
CONCLUSION—Ultrasound allows for confirmation of the clinical diagnosis and ultrasound guided injection produces a good clinical response when unguided injection is unsuccessful. The technique is quick, inexpensive, and entails no radiation exposure.

Keywords: ultrasound guided; corticosteroid injection; plantar fasciitis     

Long-Term Clinical Remission Induced by Corticosteroid Withdrawal Therapy (CSWT) in Patients with Chronic Hepatitis B Infection: A Prospective Randomized Controlled Trial—CSWT with and Without Follow-Up Interferon-α Therapy

The effectiveness of corticosteroid withdrawal therapy (CSWT), with or without follow-up interferon- (IFN-), has not been reported for HBe antigen (HBeAg) -positive patients with chronic hepatitis B. We conducted a prospective randomized controlled trial in 42 patients with HBeAg- and HBV-DNA-positive chronic hepatitis B (HBV genotype C: 38 patients) to assess the possible additive effect of follow-up IFN- after CSWT compared with CSWT alone. HBeAg seroconversion rates in the CSWT-alone and the combination group were 11.1% vs 11.8% at 24 weeks, 27.8% vs 12.5% at 52 weeks, 33.3% vs 18.8% at 76 weeks, and 38.9% vs 18.8% at 104 weeks, respectively. The final HBeAg seroconversion rates after CSWT alone were twice those following combination therapy. We conclude that CSWT alone is a very short-term treatment of just three weeks that may be more effective for long-term clinical remission than CSWT followed by IFN- in Japanese genotype C-dominant hepatitis B patients.     

Clinical pathway improves pediatrics asthma management in the emergency department and reduces admissions

Objective: Poor adherence to the National Institute of Health (NIH) Asthma Guidelines may result in unnecessary admissions for children presenting to the emergency department (ED) with exacerbations. We determine the effect of implementing an evidence-based ED clinical pathway on corticosteroid and bronchodilator administration and imaging utilization, and the subsequent effect on hospital admissions in a US ED. Methods: A prospective, interventional study of pediatric (≤21 years) visits to an academic ED between 2011 and 2013 with moderate-severe asthma exacerbations has been conducted. A multidisciplinary team designed a one-page clinical pathway based on the NIH Guidelines. Nurses, respiratory therapists and physicians attended educational sessions prior to the pathway implementation. By adjusting for demographics, acuity and ED volume, we compared timing and appropriateness of corticosteroid and bronchodilator administration, and chest radiograph (CXR) utilization with historical controls from 2006 to 2011. Subsequent hospital admission rates were also compared. Results: A total of 379 post-intervention visits were compared with 870 controls. Corticosteroids were more likely to be administered during post-intervention visits (96% vs. 78%, adjusted OR 6.35; 95% CI 3.17-12.73). Post-intervention, median time to corticosteroid administration was 45?min faster (RR 0.74; 95% CI 0.67-0.81) and more patients received corticosteroids within 1?h of arrival (45% vs. 18%, OR 3.5; 95% CI 2.50-4.90). More patients received?>?1 bronchodilator dose within 1?h (36% vs. 24%, OR 1.65; 95% CI 1.23-2.21) and fewer received CXRs (27% vs. 42%, OR 0.7; 95% CI 0.52-0.94). There were fewer admissions post-intervention (13% vs. 21%, OR 0.53; 95% CI 0.37-0.76). Conclusion: A clinical pathway is associated with improved adherence to NIH Guidelines and, subsequently, fewer hospital admissions for pediatric ED patients with asthma exacerbations.     

Association among fraction of exhaled nitrous oxide,bronchodilator response and inhaled corticosteroid type

BACKGROUND:Fraction of exhaled nitrous oxide (FeNO) is a known marker of airway inflammation and a topic of recent investigation for asthma control in children.OBJECTIVE:To investigate the relationship among FeNO and bronchodilator response measured by spirometry and types of inhaled corticosteroids (ICS).METHODS:A one-year review of children tested with spirometry and FeNO in a regional pediatric asthma centre was conducted.RESULTS:A total of 183 children were included (mean [± SD] age 12.8±2.8 years). Fluticasone was used most commonly (n=66 [36.1%]), followed by ciclesonide (n=50 [27.3%]). Most children (n=73 [39.9%]) had moderate persistent asthma. Increased FeNO was associated with percent change in forced expiratory volume in 1 s (FEV₁) after bronchodilator adjusted for allergic rhinitis, parental smoking and ICS type (B=0.08 [95% CI 0.04 to 0.12]; P<0.001). Similarly, FeNO was associated with percent change in forced expiratory flow at 25% to 75% of the pulmonary volume (FEF_25–75) after bronchodilator adjusted for parental smoking and ICS type (B=0.13 [95% CI 0.01 to 0.24]; P=0.03). FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean-adjusted FeNO was lowest in fluticasone users compared with no ICS (mean difference 18.6 parts per billion [ppb] [95% CI 1.0 to 36.2]) and there was no difference in adjusted FeNO level between ciclesonide and no ICS (5.9 ppb [95% CI −9.0 to 20.8]).CONCLUSION:FeNO levels correlated with bronchodilator response in a regional pediatric asthma centre. However, FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean adjusted FeNO varied according to ICS type, suggesting a difference in relative efficacy between ICS beyond their dose equivalents.     

Inhibitory effects of glycopyrronium,formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

BackgroundCoronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Long-acting muscarinic antagonists and β₂-agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infection-induced inflammation in the human airway are unknown.MethodsPrimary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E.ResultsPretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-β. Treatment of the cells with the CD13 inhibitor 2′2′-dipyridyl decreased viral titers. Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production. Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factor-kappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes.ConclusionsThese findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.