Interaction of Azole Compounds with DOPC and DOPC/Ergosterol Bilayers by Spin Probe EPR Spectroscopy: Implications for Antifungal Activity

The influence of two antifungal azoles, the newly synthesized compound CPA18 and the commercial drug fluconazole (FLC), on the physical state of 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine (DOPC) and DOPC/ergosterol bilayers was investigated by spin probe electron paramagnetic resonance (EPR) spectroscopy with the aim of ascertaining if direct interactions with the plasma membrane are implied in the mechanism of action against Candida albicans. 5- and 16-Doxyl-stearic acids (5-DSA and 16-DSA, respectively) were employed to this purpose, and EPR spectra were acquired in the 0 to 40 °C temperature range. Spectral line shapes were analyzed within the theory for slow motion EPR using a microscopically ordered macroscopically disordered model to describe the DOPC multilamellar vesicles and an axially symmetric Brownian model for the spin probe motion. For CPA18 remarkable changes in the molecular organization and dynamics of the phospholipid bilayers were found in the region immediately below the polar head groups, probed by 5-DSA, whereas the bilayer core, probed by 16-DSA, was only slightly affected. On the other hand, no effects of FLC on DOPC bilayers were revealed in the regions examined. Small differences were observed between DOPC and DOPC/ergosterol systems. The direct interactions of CPA18 with model membranes here highlighted may contribute to the observed fungicidal properties against both fluconazole-sensitive and -resistant C. albicans strains

Role of Omega-3 Fatty Acids in the Treatment of Depressive Disorders: A Comprehensive Meta-Analysis of Randomized Clinical Trials

<div><p>Background</p><p>Despite omega-3 polyunsaturated fatty acids (PUFA) supplementation in depressed patients have been suggested to improve depressive symptomatology, previous findings are not univocal.</p><p>Objectives</p><p>To conduct an updated meta-analysis of randomized controlled trials (RCTs) of omega-3 PUFA treatment of depressive disorders, taking into account the clinical differences among patients included in the studies.</p><p>Methods</p><p>A search on MEDLINE, EMBASE, PsycInfo, and the Cochrane Database of RCTs using omega-3 PUFA on patients with depressive symptoms published up to August 2013 was performed. Standardized mean difference in clinical measure of depression severity was primary outcome. Type of omega-3 used (particularly eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and omega-3 as mono- or adjuvant therapy was also examined. Meta-regression analyses assessed the effects of study size, baseline depression severity, trial duration, dose of omega-3, and age of patients.</p><p>Results</p><p>Meta-analysis of 11 and 8 trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo (standardized difference in random-effects model 0.56 SD [95% CI: 0.20, 0.92] and 0.22 SD [95% CI: 0.01, 0.43], respectively; pooled analysis was 0.38 SD [95% CI: 0.18, 0.59]). Use of mainly EPA within the preparation, rather than DHA, influenced final clinical efficacy. Significant clinical efficacy had the use of omega-3 PUFA as adjuvant rather than mono-therapy. No relation between efficacy and study size, baseline depression severity, trial duration, age of patients, and study quality was found. Omega-3 PUFA resulted effective in RCTs on patients with bipolar disorder, whereas no evidence was found for those exploring their efficacy on depressive symptoms in young populations, perinatal depression, primary disease other than depression and healthy subjects.</p><p>Conclusions</p><p>The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD.</p></div

Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on healthy pregnant women for prevention of post-partum depression.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on healthy pregnant women for prevention of post-partum depression.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on patients with cardiovascular disease.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on patients with cardiovascular disease.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on patients with bipolar depression.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 3 trials conducted on patients with bipolar depression.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 2 trials conducted on patients with schizophrenia.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 2 trials conducted on patients with schizophrenia.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 19 trials grouped in those conducted on patients with a DSM-defined diagnosis of major depressive disorder (MDD group, n = 11) and those on patients with an assessment of depression but not rigorously diagnosed according to the DSM criteria (non-MDD group, n = 8).

<p>Black squares: indicate the weighting given to the trial in the overall pooled estimate; lines: indicate the 95% CIs; rhombus: indicate the combined effect size.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 6 trials conducted on healthy individuals for prevention of depressive symptoms.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 6 trials conducted on healthy individuals for prevention of depressive symptoms.</p

Randomized controlled trials investigating effects of omega-3 polyunsaturated fatty acids (PUFAs) on depressed mood listed in chronological order by type of depressive disorder.

<p>AD: anti-depression; BDI: Beck Depression Inventory; CES-D: Center for Epidemiological Studies Depression Scale; CDRS: Children Depression Rating Scale; CPRS: Comprehensive Psychopathological Rating Scale; GDS: Geriatric Depression Scale; CGI: Clinical Global Impression; CGI-BP: Clinical Global Impression Bipolar; DHA: docosahexaenoic acid; E-EPA: etyl-eicosapentaenoic acid; EPDS: Edinburgh Postnatal Depression Scale; HDRS: Hamilton Depression Rating Scale; I/C: intervention/control; IDS-C: Inventory of Depressive Symptomatology Clinician; LEIDS-R: Leiden Index of Depression Severity Revised; LOT-R: Revised Life Orientation Test; MADRS: Montgomery Åsberg Depression Rating Scale; MINI: Mini International Neuropsychiatric Interview; MMSE: Mini-Mental State Evaluation; NAD: non anti-depression; NPI: Neuropsychiatric Inventory; POMS: Profile of Mood States; PPBQ: Papolos Pediatric Bipolar Questionnaire; SCID: Structural Clinical Interview for Depression; VAS: Visual Analog Score.</p

Forest plot showing individual and combined effect size estimates and 95% CIs for 2 trials conducted on patients with Alzheimer or mild cognitive impairment.

<p>Forest plot showing individual and combined effect size estimates and 95% CIs for 2 trials conducted on patients with Alzheimer or mild cognitive impairment.</p