Imbuing Aqueous Solubility to Amphotericin B and Nystatin with a Vitamin

Aqueous solubilities of many drugs in current clinical use are very low, necessitating formulations that often present problems for parenteral administration, including toxicities due to the excipients used. Recognizing that pharmacologically active compounds frequently possess amines, we asked whether pyridoxal phosphate (PLP), an inoccuous, water-soluble vitamin, could be utilized to form prodrug-like complexes via the formation of imine or iminium adducts, and whether the vitamin would impart solubilizing properties to such complexes. Direct spectroscopic and crystallographic data obtained using model primary and secondary amines showed that PLP forms stable imine adducts with primary amines under entirely aqueous conditions and at physiologic pH, while no reaction was observed for secondary amines; the basis of the exceptional stability appears to be a consequence of favorable H-bond interactions of the imine nitrogen with the 5-OH group of PLP. Amphotericin B and nystatin in their native forms display marked aqueous insolubility, and possess lone primary amines. We were able to utilize PLP in achieving excellent solubilization of both these antifungal agents, surpassing aqueous solubilities of 100 mg/mL. In in vitro bioassays, both polyenes in their PLP-adducted form display attenuated antifungal potencies which is attributable to ‘prodrug-like’ complexes. These results point to the utility of excipient-free, entirely aqueous formulations of amphotericin B for parenteral use, and may also be extended to other primary amine-bearing compounds exhibiting poor aqueous solubility

Simulation of carbon fibre composites in an industrial microwave

The ability of microwave radiation to penetrate and interact directly with materials has led to its extensive use in food and drug industries, and more recently in composites manufacturing. Microwave heating of composites allows rapid heat transfer throughout the material thickness with reduced thermal gradients and processing times as well as energy efficiency. Design of microwave systems to process composite parts with various geometries and sizes demands improved understanding of electromagnetic energy distribution and factors influencing it. Finite-element (FE) models can be efficient design tools in such cases, as physical experimentation can be impractical. In this study, a fully-coupled FE model of a carbon fibre composite in an industrial microwave environment is developed using COMSOL Multiphysics®. The effects of the heating process parameters including the number of active magnetrons, specimen thickness and the variation in the frequency of radiation on the electromagnetic field distribution are studied. The FE model showed that a substantial difference in the electromagnetic field distribution exists for the frequencies above 1 GHz compared to the lower frequencies in the microwave regime, resulting in non-uniform heating

College Students’ Sense Of Cycling Capability Deters Helmet Use: Implications For Safety Helmet Ordinances

Proponents frequently cite increased injury protection as a reason for supporting bicycle helmet ordinances; yet, many cyclists oppose such policies. In this study, six focus groups of college students discussed cycling behaviors and attitudes toward using bicycle safety helmets, and perceptions of the local helmet ordinance. The usual concerns were voiced such as “inconvenience” and “helmet hair”. Participants reported very high confidence in their cycling ability and their ability to avoid a crash which might require a helmet. They failed to take into account external factors or the actions of others which may increase risk for injury. They also did not understand how health insurance spreads the financial risk for traumatic events. These findings have implications for designing education campaigns to promote college student health, as well as initiatives for helmet ordinance advocacy.

Potent Adjuvantic Activity of a CCR1-agonistic Bis-Quinoline

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties.RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine α-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen

Synthesis of a Highly Water-Soluble Derivative of Amphotericin B with Attenuated Proinflammatory Activity

Amphotericin B (AmB), a well-known polyene antifungal agent displays a marked tendency to self-associate and, as a consequence, exhibits very poor solubility in water. The therapeutic index of AmB is low, and is associated with significant dose-related nephrotoxicity, as well as acute, infusion-related febrile reactions. Reports in the literature indicate that that toxicity of AmB may be related to the physical state of the drug. Reaction of AmB in dimethylformamide with bis(dimethylaminopropyl)carbodiimide yielded an unexpected N-alkylguanidine/N-acylurea bis-adduct of AmB which was highly water soluble. The absorption spectrum of the AmB derivative in water indicated excellent monomerization, and the anti-fungal activities of reference AmB and its water-soluble derivative against C. albicans were found to be virtually identical. Furthermore, the water-soluble adduct is significantly less active in engaging TLR4 which would suggest that the adduct may be less proinflammatory

Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood

Dark tourism and world heritage sites: a delphi study of stakeholder perceptions of the development of dark tourism products

Dark tourism has attracted increasing academic attention, but the extent to which it exists as a separate form of tourism from heritage tourism is not yet clear. Despite the growth of UNESCO World Heritage Site designations, little research has considered the relationship between dark tourism and World Heritage Sites. Because the development of dark tourism is beset with ethical concerns, heritage professionals can have negative perceptions about the acceptability or attractiveness of it for the sites that they are involved in managing. This research used a qualitative Delphi Panel method to evaluate stakeholder perceptions of the potential development of dark tourism to the Greenwich Maritime World Heritage Site in London, United Kingdom. The findings show that stakeholders are broadly supportive of tourism to the site and positive about future tourism growth. Despite this, they did not support the development of dark tourism to the site because it was perceived as inauthentic, tacky and sensationalist. In order to address this issue, recommendations are made that future attempts to develop dark tourism at WHS should involve enhancing the knowledge of stakeholders about dark tourism, and of the resources within their sites that could be included in a dark tourism offer to tourists

The Effects of Absorbing Materials on the Homogeneity of Composite Heating by Microwave Radiation

When cured in a microwave, flat thin composite panels can experience even heat distribution throughout the laminate. However, as load and geometric complexity increase, the electromagnetic field and resulting heat distribution is altered, making it difficult to cure the composite homogeneously. Materials that absorb and/or reflect incident electromagnetic radiation have the potential to influence how the field behaves, and therefore to tailor and improve the uniformity of heat distribution. In this study, an absorber was applied to a composite with non-uniform geometry to increase heating in the location which had previously been the coldest position, transforming it into the hottest. Although this result overshot the desired outcome of temperature uniformity, it shows the potential of absorbing materials to radically change the temperature distribution, demonstrating that with better regulation of the absorbing effect, a uniform temperature distribution is possible even in non-uniform composite geometries

Single-mode instability in standing-wave lasers: The quantum cascade laser as a self-pumped parametric oscillator

We report the observation of a clear single-mode instability threshold in continuous-wave Fabry-Perot quantum cascade lasers (QCLs). The instability is characterized by the appearance of sidebands separated by tens of free spectral ranges (FSR) from the first lasing mode, at a pump current not much higher than the lasing threshold. As the current is increased, higher-order sidebands appear that preserve the initial spacing, and the spectra are suggestive of harmonically phase-locked waveforms. We present a theory of the instability that applies to all homogeneously broadened standing-wave lasers. The low instability threshold and the large sideband spacing can be explained by the combination of an unclamped, incoherent Lorentzian gain due to the population grating, and a coherent parametric gain caused by temporal population pulsations that changes the spectral gain line shape. The parametric term suppresses the gain of sidebands whose separation is much smaller than the reciprocal gain recovery time, while enhancing the gain of more distant sidebands. The large gain recovery frequency of the QCL compared to the FSR is essential to observe this parametric effect, which is responsible for the multiple-FSR sideband separation. We predict that by tuning the strength of the incoherent gain contribution, for example by engineering the modal overlap factors and the carrier diffusion, both amplitude-modulated (AM) or frequency-modulated emission can be achieved from QCLs. We provide initial evidence of an AM waveform emitted by a QCL with highly asymmetric facet reflectivities, thereby opening a promising route to ultrashort pulse generation in the mid-infrared. Together, the experiments and theory clarify a deep connection between parametric oscillation in optically pumped microresonators and the single-mode instability of lasers, tying together literature from the last 60 years.United States. Defense Advanced Research Projects Agency. Spectral Combs from UV to THz Program (Grant W31P4Q-16-1-0002)National Science Foundation (U.S.) (Awards ECCS-1230477, ECCS-1614631 and ECCS- 1614531)United States. Dept. of Defense. Assistant Secretary of Defense for Research & Engineering (Air Force Contracts FA8721-05-C- 0002 and No. FA8702-15-D-0001