A near-infrared fluorescent probe based on methylene blue (p-NBMB) was developed for the detection of nitroreductase. Conjugating methylene blue with a p-nitrobenzyl moiety enables it to be activated ...by nitroreductase-catalyzed 1,6-elimination, resulting in the release of an active methylene blue fluorophore.
Many global climate models (GCMs) have difficulty in simulating climate variabilities over high northern latitudes. One of the main reasons is the inability of GCMs to simulate proper cloud fraction ...and the amount of liquid-containing cloud over the region. This study assessed the impact of cloud simulation in high latitudes by comparing the long-term parallel simulations of Community Atmosphere Model version 6 (CAM6) and CAM5, the previous version. The results show that the CAM6 simulation exhibits a considerable improvement in the Arctic, especially by reducing the cold bias of CAM5 throughout the year. Over the sub-Arctic region, however, CAM6 produces an excessive cold bias in summer and a warm bias in winter compared to the observation, which is closely related to the overestimation of cloud fraction and the amount of cloud liquid. In summer, the overestimation of the cloud in CAM6 tends to alleviate the cold bias compared to CAM5 due to an increase in downward longwave radiation over the high latitudes, while causing the excessive cold bias by blocking downward shortwave radiation over the sub-Arctic land area. In winter, when there is little incidence of shortwave radiation, the overestimation of the cloud in CAM6 increases the downward longwave radiation, which alleviates the cold bias in CAM5 over the Arctic but induces an excessive warm bias over the sub-Arctic land. The excessive cloudiness in CAM6 could weaken the high-latitude internal variability, exacerbating the deteriorating climate variability and long-term trend simulations in the region.
High-latitude low clouds in the Northern winter have been known to be closely related to the Arctic surface air temperature by controlling downward longwave radiation, but Earth system models often ...fail to accurately simulate this relationship. In this study, we conducted a series of model experiments to examine the role of winter high-latitude low-level clouds in determining the Arctic surface temperature. Our findings show that low-level clouds play a significant role in regulating the Arctic surface temperature. We used the NCAR CAM6 model and compared the results of an unforced simulation run with those of an experiment using an empirical low-level cloud scheme to alleviate the typical overestimation of the low cloud fraction of state-of-the-art general circulation models at high latitudes. The unforced simulation exhibited excessive downward longwave radiation in the Arctic, resulting in a significant warm bias compared to reanalysis data. On the other hand, the experiment using a modified scheme more closely resembled the reanalysis data in terms of low-level cloud simulation. Overall, our study underscores the importance of accurately representing low-level clouds in high-latitude regions to reduce surface temperature bias in the model.
To determine the influence of the cationization agent on the collision activated dissociation (CAD) fragmentation behavior of oligosaccharides, the CAD spectra of the singly protonated, sodiated ...oligosaccharides and singly sodiated and dibenzo-18-crown-6 ether conjugated oligosaccharides were carefully compared. Each of these three different species showed quite different fragmentation spectra. The comparison of singly protonated and sodiated oligosaccharide CAD spectra revealed that different cationization agents affected the cationization agent adduction sites as well as the fragmentation sites within the oligosaccharides. When the mobility of Na+ was limited by the dibenzo-18-crown-6 ether encapsulation agent, the examined linear oligosaccharides showed fragmentation patterns quite different from the unmodified ones. For the dibenzo-18-crown-6 ether conjugated oligosaccharides, the charge-remote fragmentation pathways were more likely to be activated than the chargedirected pathways. This work demonstrates that dibenzo-18-crown-6 ether conjugation can potentially provide a route to selectively activate the charge-remote fragmentation pathways, albeit to a limited extent, in tandem mass spectrometry studies. KCI Citation Count: 0
To determine the influence of the cationization agent on the collision activated dissociation (CAD) fragmentation behavior of oligosaccharides, the CAD spectra of the singly protonated, sodiated ...oligosaccharides and singly sodiated and dibenzo-18-crown-6 ether conjugated oligosaccharides were carefully compared. Each of these three different species showed quite different fragmentation spectra. The comparison of singly protonated and sodiated oligosaccharide CAD spectra revealed that different cationization agents affected the cationization agent adduction sites as well as the fragmentation sites within the oligosaccharides. When the mobility of $Na^+$ was limited by the dibenzo-18-crown-6 ether encapsulation agent, the examined linear oligosaccharides showed fragmentation patterns quite different from the unmodified ones. For the dibenzo-18-crown-6 ether conjugated oligosaccharides, the charge-remote fragmentation pathways were more likely to be activated than the chargedirected pathways. This work demonstrates that dibenzo-18-crown-6 ether conjugation can potentially provide a route to selectively activate the charge-remote fragmentation pathways, albeit to a limited extent, in tandem mass spectrometry studies.
Purpose
A multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of ...bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an
in vitro
release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes.
Methods
Three IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24 h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations.
Results
The rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24 h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4.
Conclusions
An accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations.
The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, Lys.sup.5, MeLeu.sup.9, Nle.sup.10-NKA.sub.(4-10), was ...examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 microg/kg IN or 2.0-6.7 mg/kg SL increased colorectal peak pressure and area under the curve. Peak bladder pressure was also increased at the same doses, and this was accompanied by highly efficient voiding at normal physiological bladder pressure. The onset of these effects was rapid (less than or equal to 2.5 min), and the primary contractions lasted ~25 min, returning to baseline in <60 min. Slight hypotension lasting a few minutes and causing <10% change from baseline was detected after higher doses and was statistically significant after only 100 microg/kg IN. In conscious dogs, there was a dose-related increase in voiding responses and reduction in the latency to urinate and defecate after 300 and 1000 microg/kg IN; emesis was also observed at these doses. SL administration of 6.7 mg/kg induced urination within 10 min, but not defecation or emesis. These findings support the feasibility of developing a convenient dosage form of small peptide NK2 receptor agonists as on-demand defecation or urination therapies.
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Injectable suspensions occasionally exhibit variations in dissolution and bioavailability, which may impact the clinical outcome of the drug product. Here, variation in the injection ...method (i.e., applied shear) for triamcinolone acetonide (TA) injectable suspension (40 mg/mL) altered the flocculation state of the particles and subsequently their dissolution. Notably, TA suspensions contained primary particles of approximately 2 µm and secondary flocculates of tens of microns. The conversion between flocculated and deflocculated particles was rapid, reversible and highly shear dependent. As such, changing shear rates during laser diffraction (LD) measurement like stirring rate, sonication, and sample introduction method (micropipette vs 25-gauge needle) may result in variability in particle size distributions (PSD) that have the potential to alter drug dissolution. Furthermore, a non-sink, discriminatory in vitro release testing (IVRT) method was developed, which combined in-situ fiber optic UV with LD to simultaneously monitor the dissolution and changing PSD of the suspension. The simultaneously measured dissolution and PSD data showed that flocculated and deflocculated particles followed different dissolution pathways. Importantly, deflocculated particles dissolved up to six times faster than the flocculated particles. Similar shear-induced changes during injection could occur in a clinical setting and have implications for drug bioavailability.
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The use of opioids for treating acute and chronic pain condition is a common clinical practice. When delivered systemically, the analgesic activity is mediated through the central ...pathway, which although effective, leads to various adverse effects such as dependence, abuse and respiratory depression. Fentanyl is an opioid analgesic that is available as injection and transdermal patch products for the management of acute and chronic pain. These products require stringent regulatory controls and label warnings on disposal due to the abuse potential associated. This research project evaluated the regional antinociceptive efficacy of fentanyl delivered from soluble microneedles. The microneedle patches were formulated with relatively less drug loading as compared to patches intended for systemic delivery and were tested for their antinociceptive activity in rats by measuring the paw withdrawal latency when exposed to a thermal stimulus. The results indicate that regional delivery of fentanyl mediated through soluble microneedles provides an effective antinociceptive activity. The onset of analgesic activity was faster with microneedle patch (0.5 h) when compared to the adhesive dermal patch (6 h). This study thus demonstrates the effectiveness of microneedle mediated pain management for immediate pain relief.
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