The aim of this paper is theophylline (THP) inclusion into xanthan-chitosan polyionic complex (Xa-CS) and the study of its in vitro and in vivo kinetic release. Xa-CS hydrogel was obtained by ionic complexation between two oppositely charged polysaccharides. THP was loaded into the Xa-CS matrix by diffusion of the drug solution. The obtained samples were characterized by FTIR spectroscopy, SEM microscopy and study of the swelling behavior. THP in vitro release experiments were carried out in conditions mimicking the gastrointestinal environment. The chosen drug dose for in vivo study was 15 mg THP/Kg body weight of THP powder or an equivalent dose in complex form. THP serum concentrations were determined by an HPLC assay. The THP peak serum concentration (C(max)) was 7.18 microg/ml for free THP and AUC(0-48) was 25.76 microg h/ml, while in the case of Xa-CS-THP, C(max) was of 5.72 microg/ml and AUC(0-48) = 45.72 microg h/ml. The in vivo study regarding the behaviour of the obtained formulation, showed an increase bioavailability of THP compared to the raw drug, suggesting the possible application of the complex Xa-CS as an oral controlled drug delivery system in the management of chronic pulmonary obstructive disease.
Partial and largely conflicting data are currently available on the interplay between obstructive sleep apnea (OSA) and hypothalamus-pituitary-adrenal axis (HPA) activity in adult obese men. This study was performed to evaluate the daily trajectories of salivary cortisol, specifically with respect to the salivary cortisol awakening response (CAR), a common method used to assess HPA axis activity. The main findings of this study were that adult male obese subjects who were newly diagnosed with severe OSA showed the following: (1) a flattening of the CAR; (2) levels of cortisol at awakening that were lower than those of the controls; and (3) maintenance of the physiological circadian activity of the HPA axis, with the highest hormone concentrations produced in the morning and the lowest in the evening. This study was also designed to investigate the effects of 3 and 6 mos of treatment with continuous airways positive pressure (CPAP). CPAP use resulted in a significant recovery of the sleep patterns disrupted by OSA; moreover, mild neuropsychological signs of depression and anxiety in severe OSA patients were concomitantly progressively improved by CPAP treatment. Furthermore, this study reports that 3 and 6 mos of CPAP therapy restored the presence of CAR and was able to significantly reduce the difference in the morning cortisol levels between the OSA and control groups. In conclusion, we report here that compared with obese nonapneic matched controls, OSA patients present a dysregulation of HPA axis activity, as shown by the flattening of the diurnal pattern of cortisol production in response to repeated challenge due to hypoxia and sleep fragmentation. This dysregulation was especially detectable in the first hour after awakening and restored after 3 and 6 mos of treatment with CPAP.
The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.
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