Optimization of polyene-azole combination therapy against aspergillosis using an in vitro pharmacokinetic-pharmacodynamic model.

Although amphotericin B-azole combination therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional in vitro tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of amphotericin B and voriconazole in an in vitro dialysis/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an azole-resistant and an azole-susceptible Aspergillus fumigatus isolate, using Bliss independence and canonical mixture response surface analyses. Amphotericin B dosing regimens with the drug administered every 24 h (q24h) were combined with voriconazole q12h dosing regimens. In vitro PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low amphotericin B-high voriconazole exposures, whereas antagonism (-6 to -16%) was found at high amphotericin B-low voriconazole exposures for both isolates. Combination therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with voriconazole/amphotericin B MICs of 1 to 4 mg/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of drug in serum (tCmin)/MIC ratio for voriconazole and a 0.5 total maximum concentration of drug in serum (tCmax)/MIC ratio for amphotericin B, whereas the equally effective monotherapy regimens required a voriconazole tCmin/MIC ratio of 1.8 and an amphotericin B tCmax/MIC ratio of 2.8. Amphotericin B-voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic drug monitoring can be employed to optimize antifungal combination therapy with low-dose (≤0.6 mg/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity.

Gluteal adipose-tissue polyunsaturated fatty-acids profiles and depressive symptoms in obese adults with obstructive sleep apnea hypopnea syndrome: a cross-sectional study.

Biomarkers of Polyunsaturated Fatty Acids (PUFAs) have been related to depressive symptoms in healthy adults. It is also known that depression is high prevalent in Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) and obesity. The aim of our study was to examine a possible association between PUFAs of the n-6 and n-3 families and depressive symptoms in obese OSAHS patients. Sixty three patients with OSAHS based on overnight attended polysomnography were included. Gluteal adipose tissue biopsies were performed in all participants. Fatty acids were analyzed by gas chromatography. Depressive symptoms were assessed by the Zung Self-rating Depression Scale. The majority of participants had grade II obesity (BMI: 36.2±4.3 kg/m(2)) and moderate to severe OSAHS. Mild depressive symptoms were found to affect 27.8% of the studied patients. No link between symptoms of depression and individual n-6 and/or n-3 PUFAs of gluteal adipose tissue was detected. However, multiple linear regression analysis showed a positive correlation between depressive symptoms and 20:3n-6/18:3n-6 ratio, and a negative association with age and n-6/n-3 ratio. The possible influence of OSAHS and obesity in depression development and the quiescent nature of gluteal adipose tissue may account for the absence of any significant relations between n-6 and/or n-3 PUFAs and depressive symptoms in our sample. The positive relationship between symptoms of depression and the particular fatty acid ratio probably indicates an increase in prostaglandins family although this needs further research.