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Limited research has been carried out to investigate the local damage features of reinforced concrete (RC) beams under close‐in explosions. To better capture the local damage features of rectangular cross‐sectional RC beams, a numerical study on the RC beams subjected to close‐in explosions based on the calibrated Karagozian & Case (K&C) concrete model was conducted in LSDYNA. First, a systematic calibration of the K&C model for concrete was performed in the single‐element numerical analysis. Calibration of the K&C model consists of parameter determination for the new strength surfaces, modification of the damage function to better feature the tensile behavior of concrete, elimination of the element size effect by introducing an element size factor and determination of the scaled damage factors. The new strength surfaces are verified and determined through both the approximation calculation method and the parameter fitting method. And the damage function was modified by reducing the termination of λ to better characterize the brittleness of concrete and feature the tensile failure. A comparison between the numerical results and the corresponding experimental results demonstrates that the calibrated K&C model and established FEM model of RC beams subjected to close‐in explosions can well characterize the local damage features of RC beams. On this basis, a further parameter analysis on the factors influencing the local damage response of RC beams was conducted by considering reinforcement details (stirrup spacing and longitudinal reinforcement diameter) and charge details (charge mass and aspect ratio). Results show that the close‐in explosions destroyed the concrete corners in the blast surface with shear stress first and the side shear failure of concrete corners weakens the concrete core strength and contributes to the greater loss of concrete core. Rear spalling damage was initially caused by the bond failure between the tensile longitudinal reinforcement and the surrounding concrete. Furthermore, increasing stirrup spacing, tensile longitudinal reinforcement diameter, and charge mass contribute to the increase in local damage sizes. [ABSTRACT FROM AUTHOR]

Evaluating Drug‐Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady‐state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4‐component transporter cocktail. This open‐label, non‐randomized, 2‐period fixed‐sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18‐55 years with body mass index 18.5‐29.9 kg/m2. During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0‐∞) and the maximum measured concentration of the analyte in plasma (Cmax), and the secondary endpoint was the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0‐tz). Steady‐state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (−2% to −9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE‐1/MATE‐2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0‐∞/Cmax/AUC0‐tz) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug‐transporter interactions in vivo. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to study the effect of load details of successive explosions on the blast behaviors of reinforced concrete (RC) beams. First, the effect of the successive loading of two identical explosions was discussed by considering the influences of standoff distance, charge mass on the failure states, and structural responses (displacement and support reaction force). And keeping the total TNT charge mass of 1 kg unchanged, the effect of loading numbers was investigated by loading two 0.5 kg TNT successively and a single 1 kg TNT on RC beams, respectively. Besides, the successive loading of two different explosions was also considered by investigating the effects of loading sequences and the first explosion induced pre‐damage on the ultimate accumulated damage of RC beams. At last, based on the reaction force and displacement responses, a nonlinear relationship between the dynamic residual load‐carrying capacity and the accumulated residual displacement was obtained to assess the damage states of the tested beams. The results show that the local failure range along the beam span direction (length of peeling‐off and length of spallation) caused by the first blast load did not apparently increase when the damaged beams were subjected to another blast load. With the increase in explosion numbers, depth of compressive crushing increases gradually. At the same stand‐off distance (from 0.25 to 0.45 m), due to the damage accumulation effect, successive loading of two 0.5 kg TNT can trigger more severe local failure but smaller accumulated residual deflection to beams than the single loading of a 1 kg TNT. Besides, when two different blast loads are loaded on tested beams, the loading sequence of the larger one first and then the smaller one (1 kg TNT/0.5 kg TNT at h = 0.45 m) can trigger larger damage to beams than the opposite loading sequence (0.5 kg TNT/1 kg TNT at h = 0.45 m). And for the beams subjected to a smaller blast load first and then a larger one, a stiffer behavior may be triggered by the second blast load on the beam after the first loading of the smaller blast load due to the residual strain in longitudinal reinforcement. Furthermore, based on the nonlinear relationship between residual load‐carrying capacity and residual displacement, the accumulated damage of RC beams was divided into mainly four phases. [ABSTRACT FROM AUTHOR]

The lift‐off characteristics of a single spherical particle in a stirred tank with transitional flow generated by a Rushton impeller have been explored in detail by using image capturing and processing techniques. We found three kinds of typical particle suspension motions, namely, the lightest PMMA particle first moves upward from the bottom center of the tank to a certain height and then spirals up to the impeller, the heavier POM particle rises to a certain height vertically and then it spirals down to the tank bottom, the still heavier PTFE and glass particles jump at random when they are rolling irregularly on the tank bottom. The single‐phase flow field of the stirred tank was measured by using 2D‐PIV technique to address the mechanism of the particle lift‐off. The random distribution of the regions with larger liquid velocity closely above the tank bottom might be the reason why the PTFE and glass particles were lifted off randomly. As for the PMMA and POM particles being lifted from the bottom center and then stagnating at a certain height, the bulk flow dominates the particle suspension. [ABSTRACT FROM AUTHOR]

Incidents caused by fire and combat operations can heat energetic materials that may lead to thermal explosion and result in structural damage and casualty, thus understanding the response of energetic materials to thermal insults is crucial for the safety design and assessment of insensitive munitions. In the present work, cookoff characteristics of a new DNAN‐based cast explosive ROL‐1 are systematically analyzed. Small‐scale slow cookoff experiments were performed and an overall reaction kinetic model including the melt‐ignition model for DNAN was developed and implemented in FLUENT. The simulated results agree well with the experimental data, which verifies the validity of the model. The large‐scale fast cookoff experiment and simulation were then performed. Ignition behaviors as well as the reaction mechanism of ROL‐1 under slow and fast cookoffs are investigated. The heat generation rates are highly correlated to the temperature gradient, liquid phase fraction, and ignition behaviors in ROL‐1. The ignition of ROL‐1 happens at around 550 K, delaying the ignition temperature of the HMX (493 K) by nearly 60 K, indicating the potential substitution of NTO for HMX. The safety of ROL‐1 has proven to stand out in comparison to a range of mixed explosives. [ABSTRACT FROM AUTHOR]

Investigations of the detonation characteristics of a new aluminized DNAN‐based melt‐cast explosive RMA‐2X (containing 30 wt.% DNAN (2,4‐dinitroanisole), 30 wt.% NTO (3‐nitro‐1,2,4‐triazol‐5‐one), 10 wt.% HMX (1,3,5,7‐tetranitro‐1,3,5,7‐tetraazacyclooctane) and 30 wt.% aluminum) were undertaken, as well as a lithium fluoride (LiF) substituted explosive RMF‐2X (containing 30 wt.% DNAN, 30 wt.% NTO, 10 wt.% HMX and 30 wt.% LiF). The interfacial velocity experiment was carried out to measure the reaction zone parameters (including the CJ pressure, the pressure at the Von Neumann spike, and the reaction zone length) of RMA‐2X. The cylinder test was also performed, and employing the test data, the detonation velocity, the Gurney energy, and the detonation energy of RMA‐2X were calculated. Investigation results are analyzed and some conclusions are drawn. The role of aluminum in the detonation characteristics are also discussed. Finally, parameters of the Jones‐Wilkins‐Lee equation of state of the detonation products were confirmed. [ABSTRACT FROM AUTHOR]

Previous studies on detonation of the Dihydroxylammonium 5,5′‐bistetrazole‐1,1′‐diolate (TKX‐50), an attractive energetic ionic salt (EIS), were mainly based on thermodynamic codes or small‐scale tests, the available experimental data are not adequate to fully understand detonation characteristics of this new kind of energetic material. This article gives an experimental investigation on detonation reaction zone (DRZ) and acceleration ability of a TKX‐50 based Polymer Bonded eXplosive (PBX), PBX‐TKX‐50. The detonation properties of two traditional explosives: (i)PBX‐HMX, an HMX‐based PBX, (ii) PBX‐RDX, an RDX‐based PBX, both of which contain the energetic compounds and binder in the same mass ratio as PBX‐TKX‐50, are also measured for a comparative analysis. The results show that PBX‐TKX‐50 has the highest detonation velocity and detonation pressure, nevertheless the slowest reaction rate within detonation reaction zone, the longest reaction time and DRZ length among the three PBX samples. Despite its prominent detonation velocity and detonation pressure, the acceleration ability of PBX‐TKX‐50 is lower than PBX‐RDX. The Jones‐Wilkins‐Lee (JWL) equation of state for detonation products calibrated by the cylinder expansion test has severely overestimated the axial acceleration ability of PBX‐TKX‐50 in the numerical simulation of Disc Acceleration eXperiment (DAX), which may due to the fact that remarkable confinement effect and/or geometry effect exist in detonation of the EIS based sample. The mechanisms behind these detonation behaviors are still under investigation in our ongoing studies. [ABSTRACT FROM AUTHOR]

To investigate the detonation characteristics of a new aluminized DNAN‐based melt‐cast explosive RDA‐2 (containing DNAN (2,4‐dinitroanisole), HMX (cyclotetramethylene tetranitramine) and aluminum), a series of cylinder tests were conducted. The LiF (lithium fluoride) explosive of a similar formulation was also tested to study the influence of aluminum on the detonation characteristics of RDA‐2. The cylinder wall expansion velocities were recorded by Photonic Doppler Velocimetry (PDV). From the experimental data, the detonation velocity, the Gurney energy, the detonation energy, and the CJ pressure of the explosives were calculated. Both the detonation velocity and CJ pressure results indicate that the aluminum seems to have no significant influence on the chemical reaction zone of RDA‐2. The experimental data shows that a large amount of aluminum reacts behind the CJ point. Finally, the parameters of the Jones‐Wilkins‐Lee (JWL) equation of the state of the detonation products were determined. [ABSTRACT FROM AUTHOR]

The reliability assessment of the projectile-borne components in a high-speed penetrator is an important issue in the penetration field. In this study, a scaling model embedded with a deceleration measurement device was used to investigate the overloading situation due to the high cost of the prototype test. The projectile could be scaled, while the deceleration measurement device needs to maintain full scale. Thus, a nonproportional scaling design is proposed to represent the rigid-body deceleration of the prototype projectile. This study, considering the mass of the deceleration measurement device, lays out the design criteria of the scaling model and carries out rigid-body deceleration similarity verification tests of the prototype and the scaling model. In addition, the rigid-body deceleration similarity was examined through model predictions and numerical simulation. These results show that the rigid-body deceleration of the nonproportional scaling model is generally in agreement with that of the prototype for penetrating the semi-infinite concrete target. The deviations of rigid-body deceleration magnitude and duration are 6.76% and −12.1%, respectively. This makes it reasonable and feasible to investigate the overloading situation of prototype projectile through a nonproportional scaling model. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80‐240 mg and multiple dosing of 240 mg once weekly over 4 weeks. Methods: Two phase 1, double‐blind, placebo‐controlled studies were conducted (single‐rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064. Results: BI 655064 showed good overall tolerability following single‐dose administration of 80‐240 mg and repeated administration of 240 mg BI 655064 over 4 weeks. More Chinese subjects reported adverse events compared with Japanese subjects following single‐dose administration (59.4% vs 3.1%). BI 655064 exhibited nonlinear, saturable kinetics, with higher doses resulting in slower apparent clearance (0.514‐0.713 mL min−1), and disproportionately higher total exposure (AUC0‐inf; 5610‐7780 μg·h mL−1) and maximum plasma concentration (15 700‐21 300 ng mL−1) with 240 mg BI 655064. Ninety percent inhibition of CD40 RO was achieved with doses ≥120 mg, and a direct relationship between BI 655064 plasma concentration and inhibition of CD40 RO was observed. Most subjects had a positive treatment‐emergent antidrug antibody response. Conclusions: BI 655064 pharmacokinetic and safety profiles in East Asian male subjects were consistent with those observed in a Western population. No adjustments in the BI 655064 dosing recommendations are warranted for future clinical trials. [ABSTRACT FROM AUTHOR]

In this paper, the stretching and rupture of liquid bridge are studied by experiment and numerical simulation. In the experiment, the relationship between the critical rupture distance of the liquid bridge and four factors, including volume of liquid bridge, particle initial distance, liquid bridge stretching velocity and liquid bridge viscosity, is quantitatively studied. It is found that the liquid bridge critical rupture distance can be described by the modified Bond number, where the critical distance shows a maximum value when this number is about 0.6. As the Capillary number of liquid bridge increases, the effect of the liquid bridge stretching velocity on the critical rupture distance increases, while the influence of the liquid bridge viscosity on the critical rupture distance increases with the volume of liquid bridge. Mesh overset is used to describe the profile change of liquid bridge, and based on the simulation the pressure field is applied in calculating the capillary fore in the liquid bridge. The rupture energy of liquid bridge can be mainly related with the Capillary number, showing two different functions when Ca = 0.01 is the turning point. Finally, two empirical formulas are proposed to predict the rupture energy of liquid bridge. [ABSTRACT FROM AUTHOR]

Explosive interaction can be originated from an inadvertent contract of molten metal and water, and most explosive accidents to date have been reported in the aluminum industry. In most cases, this incident is not a major problem to production, but do occur at some plants. Most previous work at small‐scale experiments by bringing melt droplets into a water pool, with external trigger and controlled condition. These results are difficult to extend to large‐scale events for the effect of scale. A new self‐triggering test setup to deal with ~10 kg molten aluminum for interaction under open condition was designed in this article, and the explosion energetics were first measured quantitatively. Results show that the mild explosion often occurs at relatively high aluminum/water mass ratio. Conversely, an intense explosion is more likely with higher water content. The peak temperature of intense explosion is only 247°C, and the overpressure detected in the surroundings is about 0.113 MPa. It is suggested that the carbon steel with high surface wettability could promote a spontaneous explosion, and the merely addition of metal oxide has little effect on the initiation of explosion. In view of above, two possible explosion scenarios are assessed on the superheated limit theory. [ABSTRACT FROM AUTHOR]

The experimental analyses of ignition and burning responses of mild‐impacted granular explosive, namely, cyclotrimethylene trinitramine (RDX) and cyclotetramethylene tetranitramine (HMX), were performed based on an optimized drop‐weight system equipped with a High‐Speed Camera (HSC). It has been found that jetting phenomena observed by HSC is the result of the energy released by gaseous products, which push the pulverized or melted explosives to splash radially. Jetting is the only and the most obvious difference between reactive and inert particles prior to combustion so that it can be regarded as the sign of ignition more accurately than other ways. For RDX sample, the molten phase plays an important role in the hot‐spots formation. After a piece of waxed paper is put on the glass anvil, the jetting of molten‐phase RDX will be limited due to the high‐roughness of waxed paper. Moreover, ignition growth to burning probability of RDX particles is increased compared with the non‐waxed paper case. Radial deformation velocity, jetting velocity, and flame propagation velocity have been estimated via image processing, making it possible to quantify the violence of mechanical deformation and chemical reaction. [ABSTRACT FROM AUTHOR]

A series of shock initiation experiments on the explosive PBXC03 (87 % HMX, 7 % TATB, and 6 % Viton by weight) with different particle sizes and porosities under various shock loadings have been performed, and it is found that the particle size and the porosity of the explosives have much influence on the shock initiation characteristics. That is, the smaller the particle size, the more difficult the explosive to be ignited but the faster the detonation grows once the explosive is ignited. It is also found that the detonation grows the fastest in the explosive with moderate porosity. Moreover, a modified mesoscopic reaction rate model based on the experimental results and the pore collapse hot‐spot ignition mechanism is developed, which allows for a separate reaction mechanism evaluation at different reaction stages for the shock initiation and detonation growth processes in the explosives. The calculated pressure‐time histories and Pop‐Plots for PBXC03 are founded to be all in good agreement with the experimental data. The modified mesoscopic reaction rate model shows its potentiality for quantitatively predicting the effects of the mesostructure of PBXs on the shock initiation and detonation growth processes with a high degree of confidence. [ABSTRACT FROM AUTHOR]

Mechanical performance is significant for the application of pressed polymer bonded explosives (PBXs) materials. In this research, several types of 2,6‐diamino‐3,5‐dinitropyrazine‐1‐oxide (LLM‐105) were selected to study the effects of crystal quality and morphology on the mechanical performance of LLM‐105 based PBXs. The surface bonding status of the LLM‐105 crystal and molding powder was characterized by scanning electron microscopy (SEM) and contact angle analysis, and the moldability was evaluated by determining the relative density of pressed cylinders of corresponding PBXs. Besides, static and dynamic mechanical properties were studied and compared, presenting the compressive, tensile and creep curves. For LLM‐105 based PBXs, spherical morphology and rough surface could result improved mechanical strength and creep resistance, facilitating the structural and dimensional stability of charges. In this case, it can bring benefits for their reliability and safety performances during application. [ABSTRACT FROM AUTHOR]

This paper offers a new method for calculating the reaction rate based on the pore collapse "hot‐spot" ignition mechanism in multi‐component polymer bonded explosives (PBXs), and proposes a mesoscopic reaction rate model that allows us to predict the shock initiation and detonation behaviors of multi‐component PBXs with any explosive component proportion and explosive particle size. The pressure‐time histories in PBXC03 (87 % HMX, 7 % TATB, and 6 % Viton by weight) and PBXC10 (25 % HMX, 70 % TATB, and 5 % Kel‐F800 by weight) are calculated by using the new mesoscopic reaction rate model, and the numerical results are found to be in good agreement with the experimental data. It is found that the shock initiation and detonation behaviors of PBXC03 with the dominant component of HMX is mainly controlled by the hot‐spot ignition. The subsequent combustion reacts fast once the hot‐spot is ignited and shows an accelerated reaction characteristic. While, with the dominant component of insensitive TATB, the critical initiation pressure of PBXC10 is high enough to make almost saturated reactive hot spots just behind the precursory shock‐wave front, and the shock initiation behavior is basically determined by the combustion reaction, which is characterized by a stable reaction due to the slow combustion‐wave velocity. [ABSTRACT FROM AUTHOR]

An anisotropic elastoviscoplasticity constitutive model for β‐cyclotetramethylene tetranitramine (β‐HMX) and α‐cyclotrimethylene trinitramine single crystals (α‐RDX) is developed to analyze the thermomechanical responses under shock loading. The model considers nonlinear, pressure and temperature dependent elasticity, and dislocation‐based plasticity which incorporate regenerative multiplication and heterogeneous nucleation mechanisms. The proposed model is calibrated against experimental wave profiles of (011), (010), (100), (1‾11) , (011‾) and (111‾) orientations of HMX single crystals and (210), (100), (111‾) , (21‾0) and (111) orientations of RDX single crystals. The model can well capture elastoplastic double wave structure, stress relaxation after the Hugoniot elastic limit as well as the arrival of plastic wave. Moreover, pressure, accumulated shear strain, and temperature contours of both HMX and RDX show obvious anisotropy and non‐uniform spatial distribution, which is explained by analyzing dislocation activity with corresponding resolved shear stress on slip systems. Results provide insights into understanding ignition mechanisms and predicting ignition sensitivity of explosive single crystals as well as polymer bonded explosives at the mesoscale. [ABSTRACT FROM AUTHOR]

In this paper, a complicated single-degree-of-freedom (SDOF) approach was developed to determine the global response of steel columns under combined axial and blast-induced transverse loads. Nonlinear section and member analyses were incorporated into the suggested SDOF method to account for the complex features of the material behavior, the high strain rate effect, and the column geometry. The SDOF technique was validated through comparisons with available finite element and experimental data, and a good consistency was obtained. Then, the validated SDOF approach was utilized to derive the pressure-impulse curves under various levels of axial loading. The level of the axial load was shown to have a significant influence on the dynamic behavior of a steel column subjected to a blast load. [ABSTRACT FROM AUTHOR]

Abstract: Dynamic responses of several orientations of cyclotetramethylene tetranitramine (HMX) and cyclotrimethylene trinitramine (RDX) single crystals were investigated by using plate impact experiments. The orientations studied included (011), (010), (100), (−111), (01−1), and (11−1) planes of HMX single crystals and (210), (100), (11−1), (2−10), and (111) planes of RDX single crystals. Crystal/window interface particle velocity profiles, which were measured by using velocity interferometer system for any reflector, showed distinct elastic‐plastic double‐wave structures. Dynamic mechanical properties were obtained according to impedance matching method. Elastic‐plastic responses of HMX and RDX exhibited strong anisotropy, nonlinear elasticity, and pressure/strain‐rate dependency. Anisotropy was explained by analyzing the relationship between the impact plane and deformation systems. Results revealed insights into ignition mechanisms and impact sensitivity and provided multiple data for calibration of physical‐based constitutive models. [ABSTRACT FROM AUTHOR]

Abstract: Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single‐centre, open‐label, fixed‐sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co‐administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co‐administered with FDV was similar to CsA alone. However, the AUCτ,ss and Cmax,ss of FDV were increased by 23% and 41%, respectively, when FDV was co‐administered with CsA. Exposure to TAC was slightly increased (AUC0‐∞ increased by 27%, no change in Cmax) when TAC was co‐administered with FDV. In contrast, exposure to FDV co‐administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed. [ABSTRACT FROM AUTHOR]

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P-450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady-state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single-center, open-label, fixed-sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1-3 and days 10-12. Concomitant administration with faldaprevir led to approximately 9-fold and 34-fold increases in AUC0-∞ and Cmax, respectively, of atorvastatin and approximately 15-fold and 33-fold increases in AUC0-∞ and Cmax, respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho-hydroxyatorvastatin and N-desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug-drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided. [ABSTRACT FROM AUTHOR]

Determining the mechanism of transition from projectile-impact ignition to detonation is a complex and difficult task with strong practical applications. Ignition due to low-velocity projectile impact cannot be properly explained by the available theories. We attempted to determine the mechanisms of initiation of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX)-based polymer-bonded explosives (PBXs) in a range of high temperatures, which have rarely been investigated. Comparing the shock initiation results, we found that the low-velocity projectile impact response mechanisms for a heated explosive are much more complex. Our results show that the impact ignition threshold velocity of the heated explosive does not always decrease with increasing temperature as commonly expected. A temperature dependent plastic power during impact controls the ignition in the range of 25 °C to 75 °C. At 190 °C and 200 °C, there was a sharp rise of reaction degree induced by β→δ phase transition for high HMX-content PBX. Conversely, such phase transition effect becomes insignificant for low (<50 %) HMX-content PBX. Our results show that three competing mechanisms affect the impact safety for a high HMX-content PBX at high temperature, including plastic power, temperature sensitizing, and phase transition. [ABSTRACT FROM AUTHOR]

Hydroxyl-terminated polybutadiene (HTPB) based propellants containing fixed aluminum content (18 wt %) and different amounts of organic fluoride (OF) additive were studied. Explosion heat of propellant samples and particle size distribution of the solid combustion products were experimentally measured to generally assess the effect of the organic fluoride compounds on propellants. Heats of explosion decreased approximately by 9.5 %, from 7209 (±259) to 6525 (±146) kJ kg−1, with the increase in OF content from 0 % to 6 %, and the volume fraction of particles size above 10 μm was sharply decreased. In addition, scanning electron microscope images showed the solid combustion products to be well separated, the titration analysis results also gave the amount of unburned metallic aluminum decreased. These results indicated that OF as an additive would be helpful to reduce agglomeration in the combustion products of aluminized HTPB propellants. Furthermore, a mechanism for suppression of agglomerate size can be postulated based on the X-ray diffraction analysis data that addition of OF promotes increased content of γ-Al2O3 (aluminum oxide) in the solid combustion products. [ABSTRACT FROM AUTHOR]

The β→δ phase transition (PT) of cyclotetramethylene tetranitramine (HMX) plays an important role in the safety of explosives when they are exposed to heat. In this work the effect of HMX content on the PT of HMX in Polymer Bonded Explosive (PBX) is reported. Using in situ X-ray diffraction (XRD) test combined with quantitative analysis, the dependence of the PT temperature and dynamic behavior of HMX in PBX formulations [HMX+triaminotrinitrobenzene (TATB)+Olefin] on the content of HMX is investigated. The results show that the β→δ PT temperature gradually increases with the reduction of HMX content and with the increase of TATB content. Additives of TATB and olefin in high concentration can form compact coatings on the HMX crystals. Such coatings can delay the nucleations of δ-HMX by inhibiting the volumetric expansion during PT. Moreever, these coatings separate the HMX crystals and build up a heat conduction obstacle. As a result the growths of δ-HMX are also suppressed by the coatings. In contrast, fewer additives lead to larger free surface area of HMX, which accelerates the PT. [ABSTRACT FROM AUTHOR]

During warhead penetration, which lasts several milliseconds, warheads undertake moderate pressures reaching hundreds of MPa. Previous methods have been unable to mimic such stimuli to evaluate the safety of ammunitions. Hence, new safety evaluation methods with moderate pressures and long durations to assess the stability of the explosive charges during actual penetrations are needed. Based on existing explosives safety estimation technologies and preliminary understanding of overload environments during penetration, a confined impact model was developed. The peak stimuli pressure is more than 0.3 GPa and the duration of the pressure is between 1 to 3 milliseconds. Various scales of a polymer-bonded explosive (PBX-9) were subjected to this confined impact test to study the response characteristics. The ignition mechanism of PBX-9 was obtained by synthesizing results from X-ray photoelectron spectroscopy (XPS), computed tomography (CT) scanning, differential scanning calorimetry (DSC) and thermalgravimetric analysis (TG). It was found that cracks formed on the surface during impact and the initial ignition of PBX-9 is mainly due to the decomposition of Ammonium perchlorate (AP) and hydroxyl-terminated polybutadiene (HTPB) on the interface at low temperature. Our study indicates that the designers of the PBX formulation should try to control the early decomposition of AP and HTPB in order to let the PBX survive the penetration. [ABSTRACT FROM AUTHOR]

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUCτ,ss and Cmax,ss, respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure. [ABSTRACT FROM AUTHOR]

The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r–alone group) were also pooled with group B subjects from 3 similar phase I drug–drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC0-12,ss) and steady-state maximum measured plasma concentration over a dosing interval (Cmax,ss) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C12,ss) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355. [ABSTRACT FROM PUBLISHER]

To explore the steady-state pharmacokinetic profile after coadministration of galantamine and risperidone, an open-label, randomized, single-center, two-way crossover drug-drug interaction study was conducted in 16 healthy elderly subjects, ages 60 years and older. The results showed that risperidone, when administered with galantamine, did not change the bioavailability of galantamine at steady state. In addition, systemic exposure of risperidone active moiety (risperidone plus 9-hydroxyrisperidone), the most clinically relevant component of risperidone treatment, was not affected by galantamine coadministration, while systemic exposure was increased by approximately 10% for risperidone and decreased by about 10% for 9-hydroxyrisperidone (active metabolite of risperidone). Galantamine and risperidone were both safe and well tolerated administered either alone or together. Thus, no dose adjustment for either risperidone or galantamine is necessary when these two drugs are administered together in the dose range evaluated. [ABSTRACT FROM PUBLISHER]

The aim ofthis study was to compare the pharmacokinetics ofgalantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups ofhealthy Japanese (n = 13; 6 males and 7 females) and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses ofgalantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses ofgalantamine (4 and 8 mg), and there was an approximate dose proportionality ofgalantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (± SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC0-∞) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CI] = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI = 90-127) and 108% (90% CI = 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit ofbioequivalence. Analysis ofvariance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because ofadverse events. No consistent or clinically relevant pattern ofblood chemistry, hematology, or cardiovascular changes was seen. These results suggest that the pharmacokinetic profiles of galantamine after single-dose administration are not statistically significantly different between Caucasian and Japanese groups. Galantamine was well tolerated. The safety and tolerability of galantamine were very similar in the two ethnic groups. [ABSTRACT FROM PUBLISHER]

The inside cover picture shows the effect of organic fluoride on combustion agglomerates of aluminized HTPB solid propellants. The particle size of solid combustion products were sharply decreased and agglomerates were well‐depressed, enhancement of γ‐Al2O3 formation in the propellant combustion products and the release of small gaseous molecules by OF at high temperatures pushes organic fluoride great potential in depressing agglomeration. Details are discussed in the article by Xuyuan Zhou et al. on page 417. [ABSTRACT FROM AUTHOR]