Amorphous solid dispersions (ASD) of a poorly soluble water-soluble VR1 antagonist (AMG 517) were explored for improving physical stability and in vivo exposure. AMG 517 was incorporated at 15 or 50 ...wt % into polymeric microparticles of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC) by spray-drying. Solid particles having a collapsed, corrugated structure were observed by SEM. Median particle size ranged from 29 to 40 μm by laser light scattering, and residual solvent levels were below 2% by thermal gravimetric analysis. ASD powders exhibited single glass transition temperatures (T g) in the range of 98−117 °C by modulated DSC and were amorphous by XRPD. Amorphous stability, characterized at 40 °C/75% RH (open dish) by XRPD, was at least six months for ASD formulations. Drug dissolution and supersaturation testing in a USP-2 apparatus indicated superior performance of ASD formulations over micronized AMG 517. PK of an ASD formulation in capsule (15 wt % AMG 517 in HPMCAS blended with 5 wt % SDS) in cynomolgus monkeys (n = 6, crossover) increased AUC 163% and C max 145% in comparison to an OraPlus suspension control. The study demonstrates the ASD approach provides improved amorphous physical stability and oral bioavailability for a poorly soluble development-stage molecule.
The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to ...market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of ∼19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10g) approaches. Larger batches were subsequently manufactured to confirm predictions.
Nitric oxide (NO) is an intra- and extracellular messenger that mediates diverse signaling pathways in target cells and is known to play an important role in many physiological processes including ...neuronal signaling, immune response, inflammatory response, modulation of ion channels, phagocytic defense mechanism, penile erection, and cardiovascular homeostasis and its decompensation in atherogenesis. Recent studies have also revealed a role for NO as signaling molecule in plant, as it activates various defense genes and acts as developmental regulator. In plants, NO can also be produced by nitrate reductase. NO can operate through posttranslational modification of proteins (nitrosylation). NO is also a causative agent in various pathophysiological abnormalities. One of the very important systems, the cardiovascular system, is affected by NO production, as this bioactive molecule is involved in the regulation of cardiovascular motor tone, modulation of myocardial contractivity, control of cell proliferation, and inhibition of platelet activation, aggregation, and adhesion. The prime source of NO in the cardiovascular system is endothelial NO synthase, which is tightly regulated with respect to activity and localization. The inhibition of chronic NO synthesis leads to neurogenic and arterial hypertensions, which later contribute to development of myocardial fibrosis. Overall, the modulation of NO synthesis is associated with hypertension. This review briefly describes the physiology of NO, its synthesis, catabolism, and targeting, the mechanism of NO action, and the pharmacological role of NO with special reference to its essential role in hypertension.
An encephalitis outbreak in 2003 in children from India was attributed to Chandipura virus. Sequence analyses of G, N, and P genes showed 95.6%-97.6% nucleotide identity with the 1965 isolate (G ...gene, 7-11 amino acid changes); N and P genes were highly conserved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors describe their initial experience with the adjunctive use of Glubran 2, a cyanoacrylate glue, in the embolization of the internal iliac artery (IIA). Glubran 2 was used in five patients ...as an adjunct to traditional techniques in the repair of isolated IIA aneurysms and to prevent retrograde perfusion of the aneurysm sac in the endovascular repair of aortoiliac aneurysms.
Raindrop size distribution (DSD) information is fundamental in understanding the precipitation microphysics and quantitative precipitation estimation, especially in complex terrain or urban ...environments which are known for complicated rainfall mechanism and high spatial and temporal variability. In this study, the DSD characteristics of rainy seasons in the Beijing urban area are extensively investigated using 5-year DSD observations from a Parsivel2 disdrometer located at Tsinghua University. The results show that the DSD samples with rain rate < 1 mm h−1 account for more than half of total observations. The mean values of the normalized intercept parameter (log 10Nw) and the mass-weighted mean diameter (Dm) of convective rain are higher than that of stratiform rain, and there is a clear boundary between the two types of rain in terms of the scattergram of log 10Nw versus Dm. The convective rain in Beijing is neither continental nor maritime, owing to the particular location and local topography. As the rainfall intensity increases, the DSD spectra become higher and wider, but they still have peaks around diameter D∼0.5 mm. The midsize drops contribute most towards accumulated rainwater. The Dm and log 10Nw values exhibit a diurnal cycle and an annual cycle. In addition, at the stage characterized by an abrupt rise of urban heat island (UHI) intensity as well as the stage of strong UHI intensity during the day, DSD shows higher Dm values and lower log 10Nw values. The localized radar reflectivity (Z) and rain rate (R) relations (Z=aRb) show substantial differences compared to the commonly used NEXRAD relationships, and the polarimetric radar algorithms R(Kdp), R(Kdp, ZDR), and R(ZH, ZDR) show greater potential for rainfall estimation.
In patients with ischemic stroke and a proximal cerebral arterial occlusion and salvageable tissue on imaging, alteplase followed by thrombectomy with a stent retriever was more effective than ...alteplase alone in improving reperfusion, neurologic recovery, and functional outcome.
The results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial,
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which showed reduced disability among patients with ischemic stroke who were treated with endovascular thrombectomy in addition to standard care, represent an advance in stroke care. The MR CLEAN study followed several trials that had neutral findings with respect to the use of endovascular thrombectomy.
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In the largest of these trials, the Interventional Management of Stroke 3 (IMS-3) study, investigators compared the administration of 0.9 mg of alteplase per kilogram of body weight to a bridging strategy of . . .
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