Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and safety in the treatment of major depressive disorder (MDD).
In this randomized, double-blind trial, patients age
≥
18 meeting ...DSM-IV criteria for MDD were randomized to placebo (
N
=
99), duloxetine 80 mg/day (
N
=
93), duloxetine 120 mg/day (
N
=
103), or paroxetine 20 mg/day (
N
=
97). The primary outcome measure was mean change from baseline in the 17-item Hamilton rating scale for depression (HAMD
17) total score after 8 weeks of treatment; a number of secondary efficacy measures also were assessed. Safety and tolerability were assessed via collection and analysis of treatment–emergent adverse events (TEAEs), vital signs, and weight. The Arizona sexual experiences scale was used to assess sexual functioning. Patients who had a
≥
30% reduction from baseline in the HAMD
17 total score at the end of the acute phase entered a 6-month continuation phase where they remained on the same treatment as they had taken during the acute phase; efficacy and safety/tolerability outcomes were assessed during continuation treatment.
More than 87% of patients completed the acute phase in each treatment group. Duloxetine-treated patients (both doses) showed significantly greater improvement (
P
<
0.05) in the HAMD
17 total score at week 8 compared with placebo. Paroxetine was not significantly different from placebo (
P
=
0.089) on mean change on the HAMD
17. Duloxetine 120 mg/day also showed significant improvement on most secondary efficacy measures (six of nine) compared with placebo while duloxetine 80 mg/day (three of nine) and paroxetine (three of nine) were significantly superior to placebo on fewer secondary measures. HAMD
17 mean change data from this study and an identical sister study were pooled as defined a priori for the purposes of performing a non-inferiority test versus paroxetine. Both duloxetine doses met statistical criteria for non-inferiority to paroxetine. TEAE reporting rates were low in all treatment groups and no deaths occurred in the acute or continuation phases.
The efficacy of duloxetine at doses of 80 and 120 mg/day in the treatment of MDD was demonstrated. Tolerability, as measured by TEAEs, and safety were similar to paroxetine 20 mg/day and consistent with previous published data on duloxetine in the treatment of MDD.
Display omitted
ABCG2/BCRP is an ABC transporter that plays an important role in tissue protection by exporting endogenous substrates and xenobiotics. ABCG2 is of major interest due to its ...involvement in multidrug resistance (MDR), and understanding its complex efflux mechanism is essential to preventing MDR and drug-drug interactions (DDI). ABCG2 export is characterized by two major conformational transitions between inward- and outward-facing states, the structures of which have been resolved. Yet, the entire transport cycle has not been characterized to date. Our study bridges the gap between the two extreme conformations by studying connecting pathways. We developed an innovative approach to enhance molecular dynamics simulations, ‘kinetically excited targeted molecular dynamics’, and successfully simulated the transitions between inward- and outward-facing states in both directions and the transport of the endogenous substrate estrone 3-sulfate. We discovered an additional pocket between the two substrate-binding cavities and found that the presence of the substrate in the first cavity is essential to couple the movements between the nucleotide-binding and transmembrane domains. Our study shed new light on the complex efflux mechanism, and we provided transition pathways that can help to identify novel substrates and inhibitors of ABCG2 and probe new drug candidates for MDR and DDI.
The Human Dopamine Transporter (hDAT) plays an essential role in modulating the Influx/Efflux of dopamine, and it is involved in the mechanism of certain neurodegenerative diseases such as ...Parkinson's disease. Several studies have reported important states for Dopamine transport: outward-facing open state (OFo), the outward-facing closed state (OFc), the holo-occluded state closed (holo), and the inward-facing open state (IFo). Furthermore, experimental assays have shown that different phosphorylation conditions in hDAT can affect the rate of dopamine absorption. We present a protocol using hybrid simulation methods to study the conformational dynamics and stability of states of hDAT under different phosphorylation sites. With this protocol, we explored the conformational space of hDAT, identified the states, and evaluated the free energy differences and the transition probabilities between them in each of the phosphorylation cases. We also presented the conformational changes and correlated them with those described in the literature. There is a thesis/hypothesis that the phosphorylation condition corresponding to NP-333 system (where all sites Ser/Thr from residue 2 to 62 and 254 to 613 are phosphorylated, except residue 333) would decrease the rate of dopamine transport from the extracellular medium to the intracellular medium by hDAT as previously described in the literature by Lin et al., 2003. Our results corroborated this thesis/hypothesis and the data reported. It is probably due to the affectation/changes/alteration of the conformational dynamics of this system that makes the intermediate states more likely and makes it difficult to initial states associated with the uptake of dopamine in the extracellular medium, corroborating the experimental results. Furthermore, our results showed that just single phosphorylation/dephosphorylation could alter intrinsic protein motions affecting the sampling of one or more states necessary for dopamine transport. In this sense, the modification of phosphorylation influences protein movements and conformational preferences, affecting the stability of states and the transition between them and, therefore, the transport.
Display omitted
•Protocol with MDeNM and MSM (PyEMMA) to enhance the conformational space and energy landscape for hDAT.•Distinct phosphorylations for hDAT trigger change on the stability of hDAT metastases described in the literature.•The change on the stability of metastases can explain the different rates for the transport of Dopamine.•Different patterns of phosphorylations for hDAT change its collective motions and structural dynamics.
The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Several Mpro mutations were found in SARS-CoV-2 variants, which are related to ...higher transmissibility, pathogenicity, and resistance to neutralization antibodies. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. In this study, we used a hybrid simulation method to generate intermediate structures along the six lowest frequency normal modes and sample the conformational space and characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutations, including mutations found in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. We tried to contribute to the elucidation of the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro. A machine learning analysis was performed following the investigation regarding the influence of the K90R, P99L, P108S, and N151D mutations on the dimeric interface assembling of the SARS-CoV-2 Mpro. The parameters allowed the selection of potential structurally stable dimers, which demonstrated that some single surface aa substitutions not located at the dimeric interface (K90R, P99L, P108S, and N151D) are able to induce significant quaternary changes. Furthermore, our results demonstrated, by a Quantum Mechanics method, the influence of SARS-CoV-2 Mpro mutations on the catalytic mechanism, confirming that only one of the chains of the WT and mutant SARS-CoV-2 Mpros are prone to cleave substrates. Finally, it was also possible to identify the aa residue F140 as an important factor related to the increasing enzymatic reactivity of a significant number of SARS-CoV-2 Mpro conformations generated by the normal modes-based simulations.
Display omitted
•Single surface mutations lead to changes in SARS-CoV-2 Mpro structural dynamics.•SARS-CoV-2 Mpro mutants can be more stable than wild-type SARS-CoV-2 Mpro according to the structural dynamics properties.•SARS-CoV-2 Mpro mutations can present a distinct reactivity concerning the wild-type.•Potential viral markers for more pathogenic or transmissible SARS-CoV-2 variants.
Abstract Background Patients with depression often experience pain. There is limited understanding of the relation between pain and other symptoms (depressive, anxious and non-painful somatic ...symptoms). This exploratory study assesses pain severity and interference of pain with functioning in a clinically depressed population and investigates the relation between the different groups of symptoms. Methods FINDER was a 6-month prospective, observational study investigating health-related quality of life of outpatients with depression initiating antidepressant treatment. Patients completed ratings on the Hospital Anxiety and Depression Scale (HADS), Somatic Symptom Inventory (SSI-28), and overall pain severity and interference of pain with functioning using Visual Analogue Scales (VAS) at baseline and at 3 and 6 months. Regression analyses identified factors associated with overall pain severity and interference of pain with functioning, at baseline and over the observation period. Results Of 3468 eligible patients at baseline, 56.3% experienced moderate to severe pain and 53.6% had moderate to severe pain-related interference with functioning. At 6 months of follow-up, these proportions decreased to 32.5% and 28.1%, respectively. Higher baseline SSI-somatic scores (non-painful) were strongly associated with greater pain severity and greater pain-related interference with functioning at baseline and over 6 months. Certain socio-demographic (increasing age, being unemployed) and depression-related factors (more previous episodes, longer duration of current episode) were also significantly associated with greater pain severity and interference over 6 months, while higher baseline severity of depression (HADS-D) and further education were associated with less severe pain or pain-related interference with functioning over 6 months. Conclusions Over half of depressed patients in this study experienced moderate to severe pain. Painful somatic symptoms appear to be closely related to non-painful somatic symptoms, more than to depressive or anxious symptoms suggesting that painful and non-painful somatic symptoms can be considered as one group of ‘somatic symptoms,’ all of them associated with depressive and anxious symptoms.
Abstract Background Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and ...subsequent outcomes of partial responder patients. Methods Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score >10 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort ( n =1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months. Results At 3 months, 29.4% of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI(s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission ( p <0.05). Limitations FINDER was an observational study; the current analysis was conducted post-hoc. Multivariable methods were not applied and findings are primarily descriptive and exploratory. Conclusions Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission.
The structure and proton conductivity of sulfonated styrene−ethylene copolymers have been studied. Conductivities in excess of 0.1 S/cm are obtained depending upon copolymer composition and ...sulfonation level. The dependence of conductivity on humidity has been measured and compared with that of Nafion and a partially sulfonated block copolymer. X-ray and neutron scattering studies suggest the presence of a bicontinuous network of hydrophilic and hydrophobic domains in water-swollen samples.
Summary
There is ongoing debate regarding the effectiveness of antidepressants in patients with milder major depressive disorder (MDD). This post‐hoc analysis evaluated the efficacy and tolerability ...of duloxetine in the subset of 159 (75 duloxetine and 84 placebo) patients with milder MDD (baseline HAMD17 total score ≥15 and ≤18) who were treated once daily with duloxetine 60 mg or placebo in two identical, 9‐week, randomised, double‐blind trials. At endpoint, change from baseline on HAMD17 was greater in the duloxetine group (−7.0) than in the placebo group (−4.1) (p = 0.005). Response and remission rates, and improvement on the Clinical Global Impressions‐Severity (CGI‐S) scale, the Patient Global Impressions‐Improvement (PGI‐I) scale, and measures of painful symptoms were also significantly better in the duloxetine group (p < 0.05). Tolerability was consistent with that seen in previous studies of duloxetine in patients with more severe depression. In conclusion, duloxetine 60 mg/day is effective and well tolerated in milder MDD.
The dielectric properties of proteins are central to their stability and activity. We use the Frohlich-Kirkwood theory of dielectrics to analyze two 1-ns molecular dynamics simulations of ferro- and ...ferricytochrome c in spherical droplets of 1400 water molecules. Protein and solvent are idealized as a series of concentric, spherical, dielectric media. Analysis results depend strong on the treatment of the charged protein side chains at the protein/solvent interface. If charged side chains are viewed as part of the protein medium, then the protein dipole fluctuations are dominated by large, mutually uncorrelated, anisotropic, motions of the charged side chains. It is then incorrect to view the protein region as a single, homogeneous dielectric material. If one does take this view, estimates of the protein "dielectric constant" vary from 16 to 37, depending on the exact choice of model parameters. In contrast, if the charged portions of the charged side chains are viewed as part of the solvent medium, then theory and simulation are consistent: the protein dipole fluctuations excluding charged side chains are roughly those of a homogeneous, isotropic dielectric medium, with a dielectric constant of 4.7 +/- 1.0 (ferro) or 3.4 +/- 1.0 (ferri), in agreement with powder experiments. Statistical uncertainty and sensitivity to model parameters are small. Analysis of the radial dependence of the dipole fluctuations suggests that the inner half of the protein has a somewhat lower dielectric constant of 1.5-2, consistent with its biological function in electron transfer. These results suggest that Poisson-Boltzmann models could treat the protein bulk as a low-dielectric medium and the charged surface groups as part of the solvent region
PDF
