Cocrystals of spironolactone and griseofulvin based on an in silico screening method

Cocrystal formation is considered as one of the most effective solid-state methods to alter the physicochemical properties of active pharmaceutical ingredients (APIs). In silico methods for cocrystal prediction are mostly based on structural and energetic considerations. We have developed a computational method that ranks the probability of cocrystal formation of APIs with large databases of crystal coformers (CCFs). This approach is based on using molecular electrostatic potential surfaces to assess molecular complementarity between two cocrystal components. The screening tool was applied to two low solubility drugs, namely griseofulvin and spironolactone. Promising coformer candidates were selected from a database of 310 pharmaceutically acceptable CCFs, and experimental screening was carried out. Novel solid forms were obtained by liquid-assisted grinding and were characterised by XRPD, DSC, TGA and IR. One new cocrystal of griseofulvin and two new cocrystals of spironolactone were identified, and the crystal structures were determined from the XRPD patterns. For these systems, phenols tend to act as successful H-bond donors in forming cocrystals, while carboxylic acids only give rise to physical mixtures of the two components

Incipient Separation in Shock Wave Boundary Layer Interactions as Induced by Sharp Fin

The incipient separation induced by the shock wave turbulent boundary layer interaction at the sharp fin is the subject of present study. Existing theories for the prediction of incipient separation, such as those put forward by McCabe (1966) and Dou and Deng (1992), can have thus far only predicting the direction of surface streamline and tend to over-predict the incipient separation condition based on the Stanbrook's criterion. In this paper, the incipient separation is firstly predicted with Dou and Deng (1992)'s theory and then compared with Lu and Settles (1990)' experimental data. The physical mechanism of the incipient separation as induced by the shock wave/turbulent boundary layer interactions at sharp fin is explained via the surface flow pattern analysis. Furthermore, the reason for the observed discrepancy between the predicted and experimental incipient separation conditions is clarified. It is found that when the wall limiting streamlines behind the shock wave becomes\ aligning with one ray from the virtual origin as the strength of shock wave increases, the incipient separation line is formed at which the wall limiting streamline becomes perpendicular to the local pressure gradient. The formation of this incipient separation line is the beginning of the separation process. The effects of Reynolds number and the Mach number on incipient separation are also discussed. Finally, a correlation for the correction of the incipient separation angle as predicted by the theory is also given.Comment: 34 pages; 9 figure

Temperature-dependent magnetization in diluted magnetic semiconductors

We calculate magnetization in magnetically doped semiconductors assuming a local exchange model of carrier-mediated ferromagnetic mechanism and using a number of complementary theoretical approaches. In general, we find that the results of our mean-field calculations, particularly the dynamical mean field theory results, give excellent qualitative agreement with the experimentally observed magnetization in systems with itinerant charge carriers, such as Ga_{1-x}Mn_xAs with 0.03 < x < 0.07, whereas our percolation-theory-based calculations agree well with the existing data in strongly insulating materials, such as Ge_{1-x}Mn_x. We comment on the issue of non-mean-field like magnetization curves and on the observed incomplete saturation magnetization values in diluted magnetic semiconductors from our theoretical perspective. In agreement with experimental observations, we find the carrier density to be the crucial parameter determining the magnetization behavior. Our calculated dependence of magnetization on external magnetic field is also in excellent agreement with the existing experimental data.Comment: 17 pages, 15 figure

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

The Future of Psychopharmacological Enhancements: Expectations and Policies

The hopes and fears expressed in the debate on human enhancement are not always based on a realistic assessment of the expected possibilities. Discussions about extreme scenarios may at times obscure the ethical and policy issues that are relevant today. This paper aims to contribute to an adequate and ethically sound societal response to actual current developments. After a brief outline of the ethical debate concerning neuro-enhancement, it describes the current state of the art in psychopharmacological science and current uses of psychopharmacological enhancement, as well as the prospects for the near future. It then identifies ethical issues regarding psychopharmacological enhancements that require attention from policymakers, both on the professional and on the governmental level. These concern enhancement research, the gradual expansion of medical categories, off-label prescription and responsibility of doctors, and accessibility of enhancers on the Internet. It is concluded that further discussion on the advantages and drawbacks of enhancers on a collective social level is still needed

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism

Protective effects of brain hypothermia on behavior and histopathology following global cerebral ischemia in rats

The present experiments were designed to assess whether brain hypothermia can reduce the behavioral and histopathological deficits associated with global forebrain ischemia. Animals were subjected to 12.5 min of four vessel occlusion (4VO) with moderate hypotension, and brain temperature maintained at either 37°C (4VO-37) or 30°C (4VO-30). Behavioral tests designed to assess forelimb reflexes and sensorimotor function were given on post-operative weeks 2 and 4. Beginning in week 5, the rats were trained on a variety of navigation problems in the Morris water maze. Histopathological examination of the tissue 2 months following reperfusion revealed that 4VO-30 animals sustained substantial cell death in hippocampal region CA1 and moderate damage to the dorsolateral neostriatum. 4VO-30 animals showed minimal cell death in CA1 and neostriatum. There were no group differences for any of the sensorimotor measures, or for acquisition performance on either the simple place task or visible platform version of the water maze. In contrast, during acquisition of the learning set performance of 4VO-37 animals was impaired relative to either of the other groups, whereas the performance of 4VO-30 animals was not significantly different from the sham controls. These data suggest that moderate intra-ischemic brain hypothermia provides long-lasting protection from behavioral deficits as well as neuronal injury following transient global ischemia

Combined postischemic hypothermia and delayed MK-801 treatment attenuates neurobehavioral deficits associated with transient global ischemia in rats

The present study was designed to determine whether postischemic hypothermia, delayed MK-801 (dizocilpine) administration, or a combination of these treatments can provide lasting neurobehavioral protection following transient global ischemia in rats. Rats were subjected to 10 min of normothermic (37°C) ischemia induced by 2-vessel occlusion and hypotension (50 mmHg) or sham procedures. Ischemia was followed by either: (a) 3 h at normothermic brain temperatures, (b) 3 h of postischemic brain hypothermia at 30°C, (c) hypothermia coupled with MK-801 (4 mg/kg, i.p.) on postischemic days 3, 5 and 7, or (d) postischemic MK-801 treatment alone. Neurobehavioral evaluation 6–8 weeks following surgery showed that normothermic ischemia (NI) was associated with water maze navigational deficits, including performance on a simple place task involving finding a hidden platform maintained in one position for 6 days, and a learning set task in which the platform was moved to a different location each day (both P's< 0.02 vs. sham). NI was also associated with increased locomotion in an open field ( P < 0.01 vs. sham). A combination of postischemic hypothermia and delayed MK-801 injections provided partial protection from ischemic-associated hyperactivity in the open field ( P < 0.02 vs. NI), and robust protection from simple place task deficits ( P < 0.02 vs. NI). Evidence for significant protective effects of MK-801 or hypothermia alone was observed in the learning set, during the final trial blocks each day. These results provide further evidence for neuroprotective effects of these treatments at chronic survival intervals, and indicate that the therapeutic window for attenuating ischemic damage is considerably longer than has heretofore been appreciated

Physiological demands of singing for lung health compared with treadmill walking

Introduction: participating in singing is considered to have a range of social and psychological benefits. However, the physiological demands of singing and its intensity as a physical activity are not well understood.Methods: we compared cardiorespiratory parameters while completing components of Singing for Lung Health sessions, with treadmill walking at differing speeds (2, 4 and 6 km/hour).Results: eight healthy adults were included, none of whom reported regular participation in formal singing activities. Singing induced acute physiological responses that were consistent with moderate intensity activity (metabolic equivalents: median 4.12, IQR 2.72–4.78), with oxygen consumption, heart rate and volume per breath above those seen walking at 4 km/hour. Minute ventilation was higher during singing (median 22.42 L/min, IQR 16.83–30.54) than at rest (11 L/min, 9–13), lower than 6 km/hour walking (30.35 L/min, 26.94–41.11), but not statistically different from 2 km/hour (18.77 L/min, 16.89–21.35) or 4 km/hour (23.27 L/min, 20.09–26.37) walking.Conclusions: our findings suggest the acute metabolic demands of singing are comparable with walking at a moderately brisk pace, hence, physical effects may contribute to the health and well-being benefits attributed to singing participation. However, if physical training benefits result remains uncertain. Further research including different singing styles, singers and physical performance impacts when used as a training modality is encouraged.Trial registration number ClinicalTrials.gov registry (NCT04121351)