Bosentan monohydrate and sildenafil base as two companions in enabling formulations.

HYPOTHESIS: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs. EXPERIMENTS: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs. FINDINGS: It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.

Degradation of hybrid material l,d-PLA : 5CB : SWCN under the influence of neutral, acidic, and alkaline environments.

The aim of the study was to investigate the influence of the environment's pH on the degradation of the layers of the ternary composite l,d-PLA : 5CB : SWCN (10 : 1 : 0.5, w/w/w), where l,d-PLA (poly(lactic acid)) is a biodegradable polymer, 5CB is a well-known liquid crystal (4'-pentyl-4-biphenylcarbonitrile), and SWCN are single-walled carbon nanotubes. For this purpose, the samples were stored in air, distilled water, and solutions of 0.1 M NaOH and 0.1 M HCl, for up to 62 days. Using differential scanning calorimetry, atomic force microscopy, and infra-red spectroscopy methods it was observed that for both neat l,d-PLA and composite layers there was a poor degradation process after the storage under standard air conditions, distilled water, and 0.1 M HCl solution, while the erosion of the surface layer kept in 0.1 M NaOH solution was revealed just after 6 days. The longer storage in 0.1 M NaOH solution resulted in complete degradation of the l,d-PLA polymer layer, while the composite layer survived for up to 62 days. The solubilization of the polymeric l,d-PLA matrix in the composite after 62 days was so severe that it resulted in the vanishing of thermal effects on the DSC curve except for one that was probably connected with the glass transition of the residual quantity of the polymer that remained in the layer or the isotropisation of 5CB. As a result, we have shown that admixtures of 5CB and SWCN accelerate the degradation of l,d-PLA in the composite layer due to the hydrophilic/hydrophobic interface in the layer and act as plasticizers. The mechanism of the degradation process is also discussed.

Endocrine Disrupting Chemicals in Polycystic Ovary Syndrome: The Relevant Role of the Theca and Granulosa Cells in the Pathogenesis of the Ovarian Dysfunction.

Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disorder among women of reproductive age. The pathogenesis of PCOS remains elusive; however, there is evidence suggesting the potential contribution of genetic interactions or predispositions combined with environmental factors. Among these, endocrine disrupting chemicals (EDCs) have been proposed to potentially contribute to the etiology of PCOS. Granulosa and theca cells are known to cooperate to maintain ovarian function, and any disturbance can lead to endocrine disorders, such as PCOS. This article provides a review of the recent knowledge on PCOS pathophysiology, the role of granulosa and theca cells in PCOS pathogenesis, and the evidence linking exposure to EDCs with reproductive disorders such as PCOS.

Case Report: Repeated Series of Ketamine Infusions in Patients With Treatment-Resistant Depression: Presentation of Five Cases.

Purpose: Approximately 30% of patients with major depressive disorder (MDD) are treatment resistant. There is an unquestionable need for new treatment strategies. Subanesthetic doses of intravenous (IV) ketamine have a rapid antidepressant effect in treatment-resistant depression (TRD). This paper describes the efficacy of repeated series of intravenous ketamine infusions as an add-on treatment in five TRD inpatients. Methods: Eligible patients aged 43-63 were given eight ketamine infusions as an add-on treatment for patients with MDD. The subjects have readministered the intervention due to worsening depressive symptoms. Results: Of the five inpatients given ketamine as a series of eight infusions, one underwent three, and four had two treatment series. Four patients achieved remission after first series and three after the second series of ketamine infusions. The adverse reactions were mild and transient with no sequelae. Limitations: Presented case series applies to short-term intervention with IV ketamine as an add-on therapy. The results cannot be generalized to the long-term maintenance treatment nor other ketamine formulations as well as different administration schedules and dosing. Conclusions: This case series showed efficacy and safety of the repeated series of IV ketamine treatment in TRD in MDD and bipolar disorder type I. The subsequent interventions were safe and observed adverse events were mild and transient. Interestingly, the IV ketamine treatment at successive administrations seems to alter the major depression severity of the next affective episode. There is a critical need for further research regarding IV ketamine treatment effectiveness and long-term safety in future studies.

Modifications of FLC Physical Properties through Doping with Fe2O3 Nanoparticles (Part I).

The aim of this paper is to show, by systematic studies, the influence of γ-Fe2O3 nanoparticles on the physical parameters of the liquid crystalline matrix, exhibiting a ferroelectric phase in a wide temperature range. The detailed research was carried out by using diffraction (PXRD), microscopic (OM, SEM, FCPM, POM), thermal (DSC), optical (TLI), electric and spectroscopic (FTIR) methods. We show that even the smallest concentration of γ-Fe2O3 nanoparticles largely modifies the parameters of the ferroelectric SmC* phase, such as spontaneous polarization, switching time, tilt angle, rotational viscosity, dispersion anchoring energy coefficient and helix pitch. The admixture also causes a significant reduction in the temperature of phase transitions, broadening the SmA* phase at the expense of the SmC* phase and strong streaking of the texture. We present and explain the non-monotonic modification of these parameters with an increase in the nanoparticle concentration. The influence of oleic acid admixture on these parameters is also widely discussed. We have shown that certain parameters of organic-metal nanocomposites can be controlled by the appropriate amount of metal admixture.

Magnesium in Ketamine Administration in Treatment-Resistant Depression.

Relationship between depression and magnesium levels is reported. This observational study examined whether serum magnesium concentration change over time of ketamine treatment course, also whether association between magnesium concentrations and treatment response measured with Montgomery-Åsberg Depression Rating Scale (MADRS) score occurs. Moreover, interlink between changes in Young Mania Rating Scale (YMRS) score, somatic comorbidities, and magnesium concentration was studied. Inpatients with major depressive disorder or bipolar disorder were rated weekly by clinician using MADRS and YMRS. Magnesium levels assessments were carried out weekly, before start of ketamine treatment and then every second infusion and one week after last ketamine infusion. The concentration of Mg2+ ions differs depending on the measurement. The Mg2+ concentration in pre-measurement was significantly higher than in measurement after five infusions (p = 0.031) and after seven infusions (p = 0.003). No significant correlation was observed between changes in magnesium serum levels and MADRS or YMRS. The concentration of Mg2+ ion in course of the treatment was not associated with somatic comorbidities. The study supports data for role of magnesium in treatment-resistant depression, particularly related to ketamine treatment, but provides no clear evidence of straightforward association between magnesium serum concentration and treatment response or comorbidity.

Comparison of the Dielectric Properties of Ecoflex® with L,D-Poly(Lactic Acid) or Polycaprolactone in the Presence of SWCN or 5CB.

The main goal of this paper was to study the dielectric properties of hybrid binary and ternary composites based on biodegradable polymer Ecoflex®, single walled carbon nanotubes (SWCN), and liquid crystalline 4'-pentyl-4-biphenylcarbonitrile (5CB) compound. The obtained results were compared with other created analogically to Ecoflex®, hybrid layers based on biodegradable polymers such as L,D-polylactide (L,D-PLA) and polycaprolactone (PCL). Frequency domain dielectric spectroscopy (FDDS) results were analyzed taking into consideration the amount of SWCN, frequency, and temperature. For pure Ecoflex®, two relaxation processes (α and ß) were identified. It was shown that the SWCN admixture (in the weight ratio 10:0.01) did not change the properties of the Ecoflex® layer, while in the case of PCL and L,D-PLA, the layers became conductive. The dielectric constant increased with an increase in the content of SWCN in the Ecoflex® matrix and the conductive behavior was not visible, even for the greatest concentration (10:0.06 weight ratio). In the case of the Ecoflex® polymer matrix, the conduction relaxation process at a frequency ca. several kilohertz appeared and became stronger with an increase in the SWCN admixture in the matrix. Addition of oleic acid to the polymer matrix had a smaller effect on the increase in the dielectric response than the addition of liquid crystal 5CB. Fourier transform infrared (FTIR) results revealed that the molecular structure and chemical character of the Ecoflex® and PCL matrixes remained unchanged upon the addition of SWCN or 5CB in a weight ratio of 10:0.01 and 10:1, respectively, while molecular interactions appeared between L,D-PLA and 5CB. Moreover, adding oleic acid to pure Ecoflex® as well as the binary and ternary hybrid layers with SWCN and/or 5CB in a weight ratio of Ecoflex®:oleic acid equal to 10:0.3 did not have an influence on the chemical bonding of these materials.

Modifications of EHPDB Physical Properties through Doping with Fe2O3 Nanoparticles (Part II).

The aim of our study was to analyze the influence of various concentrations of γ-Fe2O3 nanoparticles on the physical properties of the liquid crystalline ferroelectric SmC* phase, as well as to check the effect of introducing nanoparticles in the LC matrix on their properties in the prepared five nanocomposites. UV-vis spectroscopy showed that the admixture reduced the absorption of nanocomposites in the UV range, additional absorption bands appeared, and all nanocomposites were transparent in the range of 500-850 nm. The molecular dynamics in particular phases of the nanocomposites were investigated by the dielectric spectroscopy method, and it was found that nanoparticles caused a significant increase in the dielectric constant at low frequencies, a strong modification of the dielectric processes in the SmC* phase, and the emergence of new relaxation processes for the highest dopant concentrations. SQUID magnetometry allowed us to determine the magnetic nature of the nanoparticles used, and to show that the blocked state of nanoparticles was preserved in nanocomposites (hysteresis loops were also registered in the ferroelectric SmC* phase). The dependence of the coercive field on the admixture concentration and the widening of the hysteresis loop in nanocomposites in relation to pure nanoparticles were also found. In turn, the FT-MIR spectroscopy method was used to check the influence of the impurity concentration on the formation/disappearance or modification of the absorption bands, and the modification of both the FWHM and the maximum positions for the four selected vibrations in the MIR range, as well as the discontinuous behavior of these parameters at the phase transitions, were found.

Copper and Impulsivity in Ketamine Treatment for Treatment-Resistant Mood Disorders.

Treatment-resistant mood disorders, including both major depressive disorder (MDD) and bipolar disorder (BD), are challenging to treat, as limited interventions exist. Ketamine exhibits an antidepressive effect in treatment-resistant depression. Abnormal copper levels might be associated with symptoms of depression. Impulsivity is related to measures of depression, both in MDD and in BD. The aim of this paper is to explore the associations between blood copper levels and impulsivity in patients who are treatment-resistant, in the course of treatment-resistant mood disorders. The paper does not support evidence for the link between copper concentrations and impulsivity outcomes in the course of short-term ketamine treatment.

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression.

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Copper and anti-anhedonic effect of ketamine in treatment-resistant depression.

Treatment-resistant depression (TRD) remains one of the major psychiatric challenges worldwide. Search for non-monoaminergic agents, possibly effective in treatment of TRD is of prime importance. One of those agents is ketamine - a dissociative, anesthetic drug exhibiting a fast antidepressant action in patients with TRD. Concurrently, anhedonia appears to be significant symptom domain with far-reaching impact on course of treatment. There is data demonstrating that abnormal copper levels might be associated with symptoms of depression. As there is common denominator in ketamine and copper role in neurotransmission this paper is to explore the associations of blood copper levels and psychometric measures in patients with TRD in course of major depressive disorder (MDD) and bipolar disorder (BP), focusing on anhedonia measured with Snaith-Hamilton Pleasure Scale (SHAPS) score.

A geophysical, geochemical and microbiological study of a newly discovered pockmark with active gas seepage and submarine groundwater discharge (MET1-BH, central Gulf of Gdansk, southern Baltic Sea).

High-resolution bathymetric data were collected with a multi-beam echosounder in the southern part of the Baltic Sea (region MET1, Gulf of Gdansk) revealing the presence of a 10 m deep and 50 m in diameter pockmark (MET1-BH) on the sea bottom (78.7 m). To date, no such structures have been observed to reach this size in the Baltic Sea. The salinity of the near-bottom water in the pockmark was about 2 PSU (about 31.22 mmol/l Cl-), which clearly indicated the presence of a submarine groundwater discharge (SGD). Water column, sediments and the seabed structure were investigated in the MET1-BH area using various hydroacoustic devices: multi-beam and splitbeam echosounders and a sub-bottom profiler. Geochemical analyses of sediment pore waters (CH4, Cl-, Br-, F-, SO42-, Ca2+, Mg2+, K+, Na+, ∑H2S, dP, dSi, NH4+, DIC, DOC) and microbiological analysis of sediments (16S rRNA) were performed. The content of CH4 and CO2 in the outflowing gas and its origin (δ13C-CH4 and δ2D-CH4) were determined. Hydroacoustic data showed that gas was emitted intensively from the inside of the structure. The height and intensity of the gas flares varied depending on the hydrostatic pressure. The gas contained 76.1% of CH4, 17.6% of CO2 and 0.39% of He. Methane source was microbial. Geophysical investigation revealed the presence of dislocations in sub-surface sediment layers in the MET1 region, which could have created a passage for groundwater and gas. Geochemical analyses pointed to intensive processes of organic matter decomposition in this area, active methanogenesis in the surface sediment layer, lack of the sulphate-methane transition, and freshwater seepage at a depth of ~88 m (bottom of the pockmark), probably from Upper Cretaceous deposits. The Prokaryota composition, atypical for marine surface sediments, resulted from the combination of freshwater and high organic matter content, and reflected active in situ methanogensis.

Antipsychotic drugs in epilepsy.

The prevalence of various psychiatric disorders in people with epilepsy is high, with psychoses affecting 2-9% of patients. Antipsychotic drugs have been identified as increasing the risk of epileptic seizures. For first-generation antipsychotics such a risk appears to be relatively low, with the exception of chlorpromazine. Among second-generation antipsychotics, clozapine use carries the highest risk of seizure induction, while risperidone, quetiapine, amisulpride, and aripiprazole seem to pose a significantly lower risk. The incidence of an increased number of seizures is linked to the elevated blood plasma level effect of antipsychotics. To diminish the risk of seizures, it is important to start with a small dose of antipsychotic drug, to titrate slowly, to monitor serum levels of prescribed drugs, and to keep the drug at the minimal effective dose.

The immunomodulatory effect of ketamine in depression.

Major depression is one of the most frequent psychiatric conditions. Despite many available treatment methods, more than 30% of patients do not achieve remission, even after trying several antidepressants and augmentation strategies. S-enantiomer of ketamine, well-known anesthetic and analgesic, has been recently approved by Food and Drug Administration in the intranasal form as a new generation antidepressant. However, the mechanism in which ketamine reduces depressive symptoms in treatment-resistant depression patients is still not completely understood. There are several theories explaining how ketamine might reduce depressive symptoms, which have been described in detail; one of them is immunomodulatory effect of ketamine, according to the inflammatory theory of depression. In the review authors present and summarize studies showing ketamine effect on human immune system ex vivo and in vitro, including changes in cytokine levels, number, ratio and activity of various immune cell population and the correlation with clinical improvement in depressive symptoms. Most of the results confirm the anti-inflammatory effect of ketamine. There are only a few studies in the population of patients suffering from depression receiving ketamine, focused on correlation between immunological changes and clinical outcome of the therapy; further studies of that area are neccesary for understanding the immunomodulatory effect of ketamine in depression.

Suicidality in treatment resistant depression: perspective for ketamine use.

Suicidal ideations or attempts in patients with major depressive disorder (MDD) are emergent conditions that require immediate treatment. Numerous therapeutic interventions to reduce suicide risk in psychiatric disorders are effective in long-term suicide prevention, but there is necessity of sufficient, rapid pharmacological treatment of suicidal risk in MDD. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been reported to have rapid antidepressant effect. Depressive symptoms, anxiety, hopelessness, suicidal ideation had decreased within hours after ketamine infusion. Ketamine's rapid symptoms relief and reduction of suicide thoughts has aroused growing interests in psychiatric association.

Role of copper and ketamine in major depressive disorder - an update.

Major depressive disorder is one of the most important psychiatric issues worldwide, with important prevalence of treatment-resistant depression (TRD). Non-monoaminergic agents are currently in the spotlight. Objective was to explore for information about mechanisms of action of ketamine, its connections with copper and possible importance for TRD treatment. There are at least few possible pathways for ketamine action in depression in which copper and other divalent ions may show a vital role. There is urgent need for more studies to gather information about correlation between ketamine, copper and antidepressive features of these agents.

Magnesium and ketamine in the treatment of depression.

Depression affects over 121 million people annually worldwide. Relatively low remission rates among depressive patients enforce the search for new therapeutic solutions and an urgent need to develop faster-acting antidepressants with a different mechanism of action occurs. The pathomechanism of depression postulated by the monoamine hypothesis is limited. The results of abnormalities in glutamate and γ-aminobutyric acid (GABA) systems in the brains of people with mood disorders allowed to develop new theories regarding pathophysiology of these disorders. Glutamatergic transmission is influenced by magnesium and ketamine through glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonistic effects. Magnesium and ketamine have a common mechanism of action in the treatment of depression: an increase in GluN2B (NMDAR subunit) expression is related to the administration of both of the agents, as well as inhibition of phosphorylation of eEF2 (eukaryotic elongation factor 2) in cell culture and increase of the expression of BDNF in the hippocampus. Combination of ketamine and magnesium in a normal magnesium level presents a superadditive effect in depression treatment. Analysed substances affect the GABAergic system and have anti-inflammatory effects, which is correlated with their antidepressant effect. The synergistic interaction between the pharmacodynamic activity of magnesium and ketamine may be of particular importance for patients with mood disorders. Further research is needed to determine the relationship between magnesium levels and ketamine treatment response mainly in the attempt to establish if the magnesium supplementation can change ketamine treatment response time or present superadditive effect.

Efficacy of Ketamine in bipolar depression: focus on anhedonia.

Bipolar depression (BD) is among the most severe psychiatric disorders. A significant number of patients do not achieve an entirely symptom-free state and experience residual sub-syndromal depression. Most of the treatment options approved for bipolar depression give no rapid symptom improvement. Ketamine is an anaesthetic medication that acts as an antagonist of the NMDA receptor and has antidepressant potential. Due to its unique way of action, ketamine seems to be crucial for the treatment of anhedonia. This review paper aims to provide an overview of the efficacy of ketamine infusions in bipolar depression with a focus on anhedonia Literature suggests that intravenous ketamine 0.5 mg/kg over 40 min weekly could be useful in the treatment of bipolar depression with prominent anhedonia, but there is still a small number of studies that examine the efficacy of ketamine infusions in BD. In conclusion, ketamine should be considered as a valuable treatment option for patients with BD and anhedonia.

Influence of TiO2 Nanoparticles on Liquid Crystalline, Structural and Electrochemical Properties of (8Z)-N-(4-((Z)-(4-pentylphenylimino)methyl)benzylidene)-4-pentylbenzenamine.

Organic-inorganic hybrids based on liquid crystalline symmetrical imine (8Z)-N-(4-((Z)-(4-pentylphenylimino)methyl)benzylidene)-4-pentylbenzenamine (AZJ1) with two aliphatic chains and TiO2 nanomaterials were obtained and investigated taking into account thr crystallographic form of titanium dioxide i.e., anatase versus rutile. The type of TiO2 influences the mesomorphic properties of imine AZJ1, as observed by differential scanning calorimetry (DSC) and polarizing optical microscopy (POM) techniques. Fourier-Transform Infrared Spectroscopy (FT-IR) was used to investigate the interactions of oxygen vacancies located on the TiO2 surface with the studied AZJ1 imine together with studying the influence of temperature. Both imine:TiO2 anatase versus rutile hybrids possessed the highest occupied molecular orbital (HOMO) levels of about -5.39 eV (AZJ1:anatase) and -5.33 eV (AZJ1:rutile) and the lowest unoccupied molecular orbital (LUMO) levels of about -2.24 eV. The presence of TiO2 in each hybrid did not strongly affect the redox properties of imine AZJ1. Organic devices with the configuration of ITO/TiO2/AZJ1 (or AZJ1:TiO2 anatase versus rutile)/Au were fabricated and investigated in the presence and absence of visible light irradiation with a light intensity of 93 mW/cm². Finally, to analyze defects in the constructed organic devices we used thermal imaging and atomic force microscopy (AFM). The addition of TiO2 in both crystallographic forms has a positive influence on layer-forming properties that manifests itself as a very homogenous heat distribution for the whole sample.

Ketamine and magnesium common pathway of antidepressant action.

Depression is one of the major causes of disability worldwide. A proportion of adults with major depression fail to achieve remission with first-line treatment. Magnesium influences the neurotransmission involved in emotional processes, such as the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems. It has been reported that the mechanism of antidepressants' action is involved in the glutamatergic system. Theories about the role of magnesium ions in pathophysiology of major depressive disorder include blocking the glutamatergic N-methyl-D-aspartate receptor (NMDAR). Ketamine, NMDAR antagonist, was found to promote fast-acting antidepressant and antisuicidal effects. Magnesium and ketamine seem to be involved in key mechanisms of the major depression pathophysiology. The evidence in the paper discussed may indicate the synergistic interaction between magnesium and ketamine pharmacodynamic activity being of particular importance in mood disorders.