Can computer assisted diagnosis (CAD) be used as a screening tool in the detection of pulmonary nodules when using 64-slice multidetector computed tomography? Objectives: To evaluate (1) whether or not the addition of computer-assisted diagnosis (CAD) to 64-slice multidetector computed tomography (CT) can be used as a screening tool for detection of pulmonary nodules in routine CT chest examinations and (2) whether or not to advocate the incorporation of CAD as a screening tool into our daily practice. Materials and methods: A retrospective cross-sectional analysis of 109 consecutive patients who had all undergone routine contrast-enhanced CT chest examinations for indications other than lung cancer at the All examinations were evaluated in terms of the detection of pulmonary nodules by a consultant radiologist and CAD (ImageChecker CT Algorithm R2 Technology) software. The ability of CAD software to detect pulmonary nodules was evaluated against the reference standard. In addition, a chest radiologist also calculated the number of pulmonary nodules. The sensitivity and specificity of the CAD software were calculated against the reference standard by using a 2 × 2 table. The Mann−Whitney U test was applied to compare the performances of CAD and the radiologist. Results: CAD detected 610 pulmonary nodules while the radiologist detected only 113. The reference standard declared 198 pulmonary nodules to be true nodules. CAD detected 95% of all true nodules (189/198), whereas the radiologist detected only 57% (113/198). In the detection of true pulmonary nodules, CAD had 98% sensitivity compared with the radiolo-gist who had 57% sensitivity; the statistical difference between their performances had a P value ,0.001. Conclusion: Considering the high sensitivity of CAD to detect nearly all true pulmonary nodules, we advocate its application as a screening tool in all CT chest examinations for the early detection of pulmonary nodules and lung carcinoma.

International Journal of General Medicine

The properties of inhaled corticosteroids: similarities and differences.

Inhaled corticosteroids are recommended first-line therapy for persistent asthma of all severities; however, oropharyngeal and systemic adverse events can be a concern. Inhaled corticosteroids exert their therapeutic and adverse effects by interacting with glucocorticoid receptors within and outside the lungs, respectively. Ciclesonide is a novel inhaled corticosteroid that possesses a unique pharmacokinetic and pharmacodynamic profile. Ciclesonide is inactive itself and converted to its pharmacologically active metabolite, desisobutyryl-ciclesonide, in the target organ, the lungs. Pulmonary activation combined with low oral deposition may minimize oropharyngeal adverse events, and low oral bioavailability, rapid clearance, and high protein binding may reduce systemic exposure. In addition, high pulmonary deposition due to the highly respirable particles, combined with the potential for prolonged lung retention via lipid conjugation, provides for effective therapeutic action.

Pharmacokinetic and Pharmacodynamic Properties of Inhaled Ciclesonide

Ciclesonide is a new-generation inhaled corticosteroid developed to treat the inflammation associated with persistent asthma. In order to identify the properties of ciclesonide responsible for anti-inflammatory activity, ciclesonide metabolism was investigated in human lung and liver precision-cut tissue slices. Three human lung and three human liver tissue slices were incubated with 25 microM [14C]-ciclesonide for 2, 6 and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices and adenosine 5'-triphosphate content and potassium retention in liver slices. Ciclesonide and ciclesonide metabolites were analysed in tissue samples using high-performance liquid chromatography with ultraviolet and radiochemical detection. Metabolite identity was confirmed using mass spectrometry. In lung slices, the inactive parent compound, ciclesonide, was initially converted to the active metabolite, desisobutyryl-ciclesonide, and subsequently converted to fatty acid conjugates. The reversible formation of fatty acid conjugates was a major pathway of ciclesonide metabolism in human lung slices. The primary conjugate was identified as desisobutyryl-ciclesonide oleate. Ciclesonide was metabolized to at least five polar metabolites in the liver. Dihydroxylated desisobutyryl-ciclesonide was the major polar metabolite in liver slices. Activation and fatty acid esterification in the lung followed by rapid inactivation in the liver may explain the improved safety profile and prolonged anti-inflammatory activity of ciclesonide.

In Vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices.

The therapeutic effect of inhaled corticosteroids (ICS) may be affected by the metabolism of the drug in the target organ. We investigated the in vitro metabolism of beclomethasone dipropionate (BDP), budesonide (BUD), ciclesonide (CIC), and fluticasone propionate (FP) in human lung precision-cut tissue slices. CIC, a new generation ICS, is hydrolyzed by esterases in the upper and lower airways to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Lung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 μM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection. BDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP. The in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.

/pdf/in-vitro-metabolism-of-beclomethasone-dipropionate-296fdacf7y.pdf

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Objective: To investigate whether systemic exposure to desisobutyrylciclesonide (des-CIC) (the pharmacologically active metabolite of ciclesonide) and erythromycin are affected by combined administration of ciclesonide and erythromycin. Methods: 18 healthy subjects were enrolled in a Phase 1, open-label, randomized, three-period crossover study. Each subject received ciclesonide (640 μg ex-actuator, equivalent to 800 μg ex-valve, via hydrofluoroalkane metered-dose inhaler) and erythromycin (500 mg PO), separately and in combination, in random order. Blood samples were collected at timed intervals to determine serum concentrations of erythromycin, des-CIC, and ciclesonide using HPLC-MS detection. Adverse events were recorded throughout the study. Results: Combined administration of ciclesonide and erythromycin did not alter the pharmacokinetics(PK) ofeither drug. The serum concentration vs. time profiles of erythromycin, des-CIC, and ciclesonide were similar when ciclesonide and erythromycin were administered separately or together. In addition, the PK characteristics of erythromycin and des-CIC were equivalent following single or co-administration. Point estimates (90% confidence intervals (CI)) for erythromycin were as follows: AUC 0 - i n f , 0.96 (0.79, 1.18); C m a x , 1.00 (0.84, 1.20); and t 1 / 2 , 0.96 (0.83, 1.12). The following point estimates (90% Cl) were obtained for des-CIC: AUC 0 i n f , 1.16 (1.03, 1.30); C m a x , 1.06 (0.98, 1.15); and t 1 / 2 , 1.04 (0.96, 1.13). Lack of ciclesonide/erythromycin interaction was demonstrated as the 90% CI of AUC 0 - i n f , C m a x , and t 1 / 2 of both compounds were entirely within the stipulated equivalence range of 0.67 - 1.50. No study drug-related adverse events occurred during this study. Conclusions: Combined administration of cicle-sonide and erythromycin did not alter the PK properties of either drug. Both drugs were safe and well-tolerated. Therefore, systemic exposure to ciclesonide or erythromycin is not increased in patients receiving concomitant therapy.

Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin.

Objective: To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. Methods: 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 μg (ex-actuator, equivalent to 1,600 μg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry. Results: There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC ( 0 - i n f ) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t 1 / 2 ) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups. Conclusion: After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.

Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar.

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Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin.

Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar.