A stochastic version of corticosteriod pharmacogenomic model

The purpose of this study was to develop a stochastic version of corticosteriod fifth generation pharmacogenomic model. The Gillespie algorithm was used to generate the independent time courses of the receptor messenger RNA (mRNA). Initial parameters for the stochastic simulation were adapted from the study by Jin et al. The result obtained from the proposed stochastic model showed an overall agreement with the deterministic fifth generation model. This study suggested that because the stochastic model takes into account the "noise" nature of gene regulation, it would have potential application in pharmacogenomic modeling.     

Inhaled and intravenous corticosteroids both attenuate chlorine gas-induced lung injury in pigs

BACKGROUND: The accidental release of chlorine gas is a constant threat in urban areas. The purpose of this randomized, blinded, controlled experiment was to examine the effects of post-injury administration of inhaled or intravenous corticosteroid in chlorine gas-injured pigs followed for 23 h. METHODS: Anaesthetized, ventilated pigs (n = 24) in the prone position were exposed to chlorine gas (400 parts per million in air) (1160 mg/m3) for 15 min, then randomly allocated to receive inhaled budesonide (BUD) and intravenous placebo, intravenous betamethasone (BETA) and inhaled placebo or inhaled and intravenous placebo. Haemodynamics, gas exchange and lung mechanics were evaluated for 23 h after exposure to chlorine gas. RESULTS: Airway and pulmonary artery pressures increased and arterial oxygenation fell sharply (from 13.5 +/- 0.8 to 6.7 +/- 0.9 kPa, P < 0.001) after chlorine gas exposure. These immediate changes were followed by a gradual improvement over 5-7 h to a stable level of dysfunction for the rest of the experiment in placebo animals. Arterial oxygen tension, pulmonary vascular resistance and airway pressure recovered faster and more completely in the budesonide and betamethasone groups than in the placebo group (P < 0.01). Lung wet weight to dry weight ratios were greater in the placebo group than in the budesonide and betamethasone groups (6.34 +/- 0.59 vs. 5.56 +/- 0.38 and 5.53 +/- 0.54, respectively, P < 0.05). There was a trend towards lower histological injury scores compared with placebo in animals that received budesonide (P = 0.05) or betamethasone (P = 0.07). CONCLUSION: Treatment of chlorine gas lung injury with nebulized budesonide or intravenous betamethasone had similar positive effects on recovery of lung function.     

Bone mineral density in women with sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Almost any organs of the body, but mostly the lungs, are involved. Bone mineral density (BMD) can be affected directly or indirectly in chronic granulomatous systemic diseases such as sarcoidosis. The aim of our study was to evaluate BMD in premenopausal and postmenopausal sarcoidosis patients with or without prednisone treatment and to compare their BMD values with those of a control group having the same menopausal status. Thirty-five premenopausal women (18 untreated, 8 treated, and 9 controls) and 21 postmenopausal women (5 untreated, 5 treated, and 11 controls) were included in the study. All of the patients had a histologically proven diagnosis and were being followed-up at the Sarcoidosis Outpatient Clinic of our unit. BMD of the lumbar (L) spine and femoral neck was measured by dual-energy absorptiometry (DEXA). The subgroups of premenopausals and postmenopausals were compared separately. Comparison among the groups was performed by using analysis of variance. Age, duration of the disease, and body mass index were comparable in treated, untreated, and control subgroups of the pre- and postmenopausal groups, and the subgroups of postmenopausals had comparable durations since menopause. For premenopausals, BMD values at L1–4 were not significantly different among the subgroups (0.920 ± 0.08g/cm², 0.801 ± 0.09g/cm², and 0.910 ± 0.05g/cm², for untreated, treated, and controls, respectively). However, the BMD value at the femoral neck in treated patients (0.921 ± 0.1g/cm²) was significantly lower than the values in untreated patients (1.080 ± 0.2g/cm²; P 0.01) and in controls (1.028 ± 0.17g/cm²; P 0.05). For postmenopausals, the BMD value at L1–4 in controls (1.019 ± 0.07g/cm²) was significantly higher than the values in untreated patients (0.783 ± 0.01g/cm²) and in treated patients (0.751 ± 0.08g/cm²; P 0.001 for both). The BMD value at the femoral neck in controls (0.890 ± 0.1g/cm²) was higher than the values in untreated patients (0.745 ± 0.08g/cm²) and treated patients (0.747 ± 0.1g/cm²), but the difference was not statistically significant (P = 0.06). We concluded that sarcoidosis patients, especially postmenopausal patients with corticosteroid treatment, may have an increased risk of bone mineral loss. Large-scale studies are warranted in order to delineate the exact roles of the disease itself, menopausal status, and corticosteroid treatment in this bone mineral loss.     

The biology and management of subglottic hemangioma: past, present, future

OBJECTIVES/HYPOTHESIS: Objectives were 1) to review the presentation, natural history, and management of subglottic hemangioma; 2) to assess the affect of five variables (age, gender, degree of subglottic narrowing, location and extent of subglottic hemangioma, and lack or presence of other hemangioma) and the outcome of six different treatment modalities (conservative monitoring, corticosteroid, laser surgery, tracheotomy, laryngotracheoplasty, and interferon) in the management of subglottic hemangioma; and 3) to present specific guidelines to help determine the best possible treatment modality at the time of initial presentation. STUDY DESIGN: Retrospective review in the setting of three tertiary care pediatric medical centers. METHODS: Methods included 1) extensive review of the literature; 2) a systematic review with respect to age, gender, presentation, associated medical problems, location and degree of subglottic narrowing, initial treatment, need for subsequent treatments, outcome, complications, and prognosis; and 3) statistical analysis to determine the effect of five variables (age, gender, degree of subglottic narrowing, location and extent of subglottic hemangioma, and lack or presence of other hemangioma) and the outcome of six different treatment modalities (conservative monitoring, corticosteroid, laser surgery, tracheotomy, laryngotracheoplasty, and interferon). RESULTS: In all, 116 patients with a mean age of 4.7 months were treated. The most common location of subglottic hemangioma was the left side. The range of subglottic narrowing was 10% to 99% (mean percentage, 65%). Twenty-six patients (22%) were managed with a single treatment modality, which included conservative monitoring (n = 13), corticosteroid (n = 11), and tracheotomy (n = 2). Ninety patients (78%) required multimodality treatments. Overall, the treatments included conservative monitoring (n = 13), corticosteroid (n = 100), tracheotomy (n = 32), CO2 laser (n = 66), interferon (n = 5), and laryngotracheoplasty (n = 25). Complication rates included the following: conservative monitoring (none), corticosteroid (18%), tracheotomy (none), CO2 laser (12%), interferon (20%), and laryngotracheoplasty (20%). The following variables showed statistical significance in the outcome of different treatment modality: 1) degree of subglottic narrowing (P < .001), 2) location of subglottic hemangioma (P < .01), and 3) presence of hemangioma in other areas (P < .005). Gender (P > .05) and age at the time of presentation (P > .06) did not show any statistical significance on the outcome of the treatments. CONCLUSION: Each patient should be assessed comprehensively, and treatment should be individualized based on symptoms, clinical findings, and experience of the surgeon. The authors presented treatment guidelines in an attempt to rationalize the management of subglottic hemangioma and to help determine the best possible treatment modality at the time of initial presentation.     

Characterization of Suspension-Based Metered Dose Inhaler Formulations Composed of Spray-Dried Budesonide Microcrystals Dispersed in HFA-134a

PURPOSE: To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a. METHODS: Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity. RESULTS: Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 microm). The formulation was observed to maintain its performance over 6 months at 40 degrees C/75% RH and 16 months at 25 degrees C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD(4.7 microm) values approaching 400 microg can be delivered in a single inhalation. CONCLUSIONS: Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.     

Intra-amniotic corticosteroids for preterm lung maturation in sheep

OBJECTIVE: The purpose of this study was to compare efficacy on fetal lung maturation of intra-amniotic betamethasone or budesonide with the efficacy of maternal intramuscular betamethasone. STUDY DESIGN: Pregnant ewes received intra-amniotic betamethasone (0.5 mg/kg or 2 mg/kg fetal weight), intra-amniotic budesonide (0.5 mg/kg or 2 mg/kg), maternal intramuscular betamethasone (0.5 mg/kg maternal weight), intra-amniotic saline solution, or maternal saline solution. Lambs were delivered 2 or 7 days later, at 124 days of gestation for measurement of respiratory system compliance, ventilatory efficiency index, and surfactant levels. RESULTS: Lung function increased 2 days after maternal betamethasone, intra-amniotic betamethasone (2 mg/kg), and intra-amniotic budesonide (2 mg/kg) administration and 7 days after maternal betamethasone or intra-amniotic budesonide (2.0 mg/kg) administration. Lung function was not improved 7 days after intra-amniotic betamethasone (2.0 mg/kg) administration or 2 days after intra-amniotic betamethasone (0.5 mg/kg) or intra-amniotic budesonide (0.5 mg/kg) administration. Intra-amniotic corticosteroid administration increased fetal death and respiratory morbidity. CONCLUSION: Intra-amniotic corticosteroid administration improved preterm lung function, but the associated morbidity and mortality rates suggest that they are not suitable for clinical use.     

Early prophylactic inhaled beclomethasone in infants less than 1250 g for the prevention of chronic lung disease

OBJECTIVE:

Inflammation plays an important role in the development of chronic lung disease (CLD), which has become a major cause of morbidity in surviving infants less than 1250 g at birth. The authors hypothesized that the progression of this inflammation and, therefore, the establishment of CLD would be decreased with the use of early prophylactic inhaled corticosteroids. Short, and long term respiratory and neurodevelopmental outcomes were also examined.

DESIGN:

A double-blind, randomized placebo controlled trial.

SETTING:

Level-III neonatal intensive care unit.

POPULATION STUDIED:

Sixty infants less than 1250 g at birth, diagnosed with respiratory distress syndrome and requiring ventilatory support at 72 h of age were enrolled in the study.

INTERVENTION:

Infants enrolled received either placebo or beclomethasone diproprionate by a metered dose inhaler, which was used in-line with the ventilator circuit while the infant was ventilated and then via a spacer until 28 days of age.

RESULTS:

Thirty infants were given beclomethasone and 30 were given placebo. There were two deaths in each group. Among the surviving infants, the frequency of moderate-to-severe CLD was 17% in each study group. Mean time to extubation was not different for beclomethasone compared with placebo at 16.4 and 12.5 days (P=0.12), respectively. The requirement for intravenous corticosteroids was lower in the beclomethasone-treated group (RR 0.67, 95% CI 0.43 to 1.04), although this difference was not statistically significant. The incidence of growth failure, infection and intraventricular hemmorhage did not differ between the two groups. Long term outcomes were not different with respect to the incidence of respiratory re-admissions, cerebral palsy, developmental delay, blindness or deafness.

CONCLUSIONS:

Early treatment with inhaled beclomethasone diproprionate did not reduce the incidence of CLD or decrease the duration of mechanical ventilation. The decrease in intravenous corticosteroid use was not statistically significant. Long term outcome was not affected.     

Methotrexate in the management of granulomatous mastitis

Granulomatous mastitis is a rare benign inflammatory breast disease that often clinically simulates carcinoma. Surgical resection of the entire lesion has been the main method of treatment but recurrence, infection, sinus formation and delayed wound healing can occur relatively commonly. Corticosteroids are also effective in recurrent or resistant cases but are associated with side-effects and relapse of disease after steroid withdrawal. A low weekly oral dose of methotrexate was used in five resistant cases after surgery plus corticosteroid. All cases achieved remission, withdrawal of corticosteroid without relapse and no methotrexate side-effect.     

Hypertrophic pachymeningitis with anti-neutrophil cytoplasmic antibody (p-ANCA), and diabetes insipidus

We treated a patient with idiopathic cranial hypertrophic pachymeningitis and elevated serum titer of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) reactive against myeloperoxidase. This 67-year-old man showed multiple cranial nerve-palsies, central diabetes insipidus (DI), and an intrasellar mass. DI and intrasellar mass had been present for 3 years, and DI had been well controlled by intranasal desmopressin. His nerve-palsies were most likely caused by thickened dura matter detected by the brain MRI. Granuloma may develop in the sella, and MRI findings in our patient are compatible to it. Corticosteroid and oral cyclophosphamide therapy improved his neurological symptoms and serum p-ANCA level with showing good correlation. DI improved temporally for 2 months. Few other cases of hypertrophic pachymeningitis with elevated p-ANCA have been reported, however the etiology is unknown. As p-ANCA antibodies have been detected in many of vasculitides, microvasculitis may be involved in some cases of idiopathic hypertrophic pachymeningitis.