On the angular anisotropy of the randomly averaged magnetic neutron scattering cross section of nanoparticles.

The magnetic small-angle neutron scattering (SANS) cross section of dilute ensembles of uniformly magnetized and randomly oriented Stoner-Wohlfarth particles is calculated using the Landau-Lifshitz equation. The focus of this study is on the angular anisotropy of the magnetic SANS signal as it can be seen on a two-dimensional position-sensitive detector. Depending on the symmetry of the magnetic anisotropy of the particles (e.g. uniaxial, cubic), an anisotropic magnetic SANS pattern may result, even in the remanent state or at the coercive field. The case of inhomogeneously magnetized particles and the effects of a particle-size distribution and interparticle correlations are also discussed.

Magnetic neutron scattering from spherical nanoparticles with Néel surface anisotropy: atomistic simulations.

A dilute ensemble of randomly oriented non-interacting spherical nanomagnets is considered, and its magnetization structure and ensuing neutron scattering response are investigated by numerically solving the Landau-Lifshitz equation. Taking into account the isotropic exchange interaction, an external magnetic field, a uniaxial magnetic anisotropy for the particle core, and in particular the Néel surface anisotropy, the magnetic small-angle neutron scattering cross section and pair-distance distribution function are calculated from the obtained equilibrium spin structures. The numerical results are compared with the well known analytical expressions for uniformly magnetized particles and provide guidance to the experimentalist. In addition, the effect of a particle-size distribution function is modelled.

Magnetic neutron scattering from spherical nanoparticles with Néel surface anisotropy: analytical treatment.

The magnetization profile and the related magnetic small-angle neutron scattering cross section of a single spherical nanoparticle with Néel surface anisotropy are analytically investigated. A Hamiltonian is employed that comprises the isotropic exchange interaction, an external magnetic field, a uniaxial magnetocrystalline anisotropy in the core of the particle and the Néel anisotropy at the surface. Using a perturbation approach, the determination of the magnetization profile can be reduced to a Helmholtz equation with Neumann boundary condition, whose solution is represented by an infinite series in terms of spherical harmonics and spherical Bessel functions. From the resulting infinite series expansion, the Fourier transform, which is algebraically related to the magnetic small-angle neutron scattering cross section, is analytically calculated. The approximate analytical solution for the spin structure is compared with the numerical solution using the Landau-Lifshitz equation, which accounts for the full nonlinearity of the problem. The signature of the Néel surface anisotropy can be identified in the magnetic neutron scattering observables, but its effect is relatively small, even for large values of the surface anisotropy constant.

MuMag2022: a software tool for analyzing magnetic field dependent unpolarized small-angle neutron scattering data of bulk ferromagnets.

The MATLAB-based software tool MuMag2022 is presented for the analysis of magnetic-field-dependent unpolarized small-angle neutron scattering (SANS) data of bulk ferromagnets such as elemental nanocrystalline ferromagnets, magnetic nanocomposites or magnetic steels. On the basis of the micromagnetic theory for the magnetic SANS cross section, the program analyzes unpolarized total (nuclear and magnetic) SANS data within the approach-to-saturation regime. The main features of MuMag2022 are the estimation of the exchange-stiffness constant, and of the strength and spatial structure of the magnetic anisotropy field and the magnetostatic field due to longitudinal magnetization fluctuations. MuMag2022 is open source and available as a standalone executable for Windows at https://mumag.uni.lu.

Highly Active Ice-Nucleating Particles at the Summer North Pole.

The amount of ice versus supercooled water in clouds is important for their radiative properties and role in climate feedbacks. Hence, knowledge of the concentration of ice-nucleating particles (INPs) is needed. Generally, the concentrations of INPs are found to be very low in remote marine locations allowing cloud water to persist in a supercooled state. We had expected the concentrations of INPs at the North Pole to be very low given the distance from open ocean and terrestrial sources coupled with effective wet scavenging processes. Here we show that during summer 2018 (August and September) high concentrations of biological INPs (active at >-20°C) were sporadically present at the North Pole. In fact, INP concentrations were sometimes as high as those recorded at mid-latitude locations strongly impacted by highly active biological INPs, in strong contrast to the Southern Ocean. Furthermore, using a balloon borne sampler we demonstrated that INP concentrations were often different at the surface versus higher in the boundary layer where clouds form. Back trajectory analysis suggests strong sources of INPs near the Russian coast, possibly associated with wind-driven sea spray production, whereas the pack ice, open leads, and the marginal ice zone were not sources of highly active INPs. These findings suggest that primary ice production, and therefore Arctic climate, is sensitive to transport from locations such as the Russian coast that are already experiencing marked climate change.

Volcanic ash ice nucleation activity is variably reduced by aging in water and sulfuric acid: the effects of leaching, dissolution, and precipitation.

Volcanic ash nucleates ice when immersed in supercooled water droplets, giving it the potential to influence weather and climate from local to global scales. This ice nucleation activity (INA) is likely derived from a subset of the crystalline mineral phases in the ash. The INA of other mineral-based dusts can change when exposed to various gaseous and aqueous chemical species, many of which also interact with volcanic ash in the eruption plume and atmosphere. However, the effects of aqueous chemical aging on the INA of volcanic ash have not been explored. We show that the INA of two mineralogically distinct ash samples from Fuego and Astroni volcanoes is variably reduced following immersion in water or aqueous sulfuric acid for minutes to days. Aging in water decreases the INA of both ash samples by up to two orders of magnitude, possibly due to a reduction in surface crystallinity and cation availability accompanying leaching. Aging in sulfuric acid leads to minimal loss of INA for Fuego ash, which is proposed to reflect a quasi-equilibrium between leaching that removes ice-active sites and dissolution that reveals or creates new sites on the pyroxene phases present. Conversely, exposure to sulfuric acid reduces the INA of Astroni ash by one to two orders of magnitude, potentially through selective dissolution of ice-active sites associated with surface microtextures on some K-feldspar phases. Analysis of dissolved element concentrations in the aged ash leachates shows supersaturation of certain mineral species which could have precipitated and altered the INA of the ash. These results highlight the key role that leaching, dissolution, and precipitation likely play in the aqueous aging of volcanic ash with respect to its INA. Finally, we discuss the implications for understanding the nature and reactivity of ice-active sites on volcanic ash and its role in influencing cloud properties in the atmosphere.

Unraveling the magnetic softness in Fe-Ni-B-based nanocrystalline material by magnetic small-angle neutron scattering.

Magnetic small-angle neutron scattering is employed to investigate the magnetic interactions in (Fe0.7Ni0.3)86B14 alloy, a HiB-NANOPERM-type soft magnetic nanocrystalline material, which exhibits an ultrafine microstructure with an average grain size below 10 nm. The neutron data reveal a significant spin-misalignment scattering which is mainly related to the jump of the longitudinal magnetization at internal particle-matrix interfaces. The field dependence of the neutron data can be well described by micromagnetic small-angle neutron scattering theory. In particular, the theory explains the 'clover-leaf-type' angular anisotropy observed in the purely magnetic neutron scattering cross section. The presented neutron data analysis also provides access to the magnetic interaction parameters, such as the exchange-stiffness constant, which plays a crucial role towards the optimization of the magnetic softness of Fe-based nanocrystalline materials.

Pharmacokinetics of daily self-application of imiquimod 3.75% cream in adult patients with external anogenital warts.

Imiquimod 3.75% cream is a new formulation intended for daily self-application. The objective of this study was to characterize serum imiquimod pharmacokinetics under maximal use conditions. Adults with ≥8 warts or total wart area ≥100 mm² applied up to 1 packet of imiquimod 3.75% cream (250 mg cream, 9.375 mg imiquimod) once daily for 3 weeks. Blood was obtained prior to doses 1, 7, 14, and 21 and at selected time points after doses 1 and 21. Eighteen patients (13 men and 5 women) with a median wart count of 16 and total wart area of 60 mm² were enrolled. Day 21 mean (SD) serum C(max) was 0.49 (0.37) ng/mL, AUC0₋24 6.80 (3.59) ng·h/mL, and t(1/2) 24.1 (12.4) hours. Steady state was achieved by day 7 with ~2-fold increase in C(max) and AUC after multiple dosing. Overall, C(max) was higher and t(max) shorter in women, with comparable AUC0₋24. Imiquimod metabolites were sporadically quantifiable. No patients discontinued for adverse events; 1 interrupted dosing for an application site ulcer. Treatment-related adverse events occurred in 16.7% of the patients. In conclusion, serum imiquimod concentrations were low after daily self-application to external anogenital warts of up to 1 packet of imiquimod 3.75% cream for 21 days.

Comparative bioavailability of a premixed, ready-to-use formulation of intravenous amiodarone with traditional admixture in healthy subjects.

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight subjects were enrolled in this randomized, single-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration-time curve for time 0-72 hours (AUC0-72hr ) for amiodarone was 0.96 (95% confidence interval [CI], 0.94-0.99). The geometric ratio of the maximum concentration (Cmax ) for amiodarone was 0.87 (95% CI, 0.84-0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready-to-use formulation were identified.

Pharmacokinetics and platelet aggregation inhibitory effects of a novel intravenous formulation of clopidogrel in humans.

1. PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2. The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300 mg) were administered to each group (n = 24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30 min and 2, 5 and 24 h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30 min and 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. 3. PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4. These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention.

Evaluation of the effects of PM101, a cyclodextrin-based formulation of intravenous amiodarone, on blood pressure in healthy humans.

Intravenous amiodarone (AIV) is used to treat cardiac arrhythmias. Hypotension is the dose-limiting adverse event of AIV and is considered to be due to the cosolvents (polysorbate 80 and benzyl alcohol) in the formulation. To minimize hypotension, the initial loading dose of AIV (150 mg) is diluted to 1.5 mg/ml and slowly infused over 10 minutes. PM101 is a cosolvent-free intravenous formulation of amiodarone. The present study was designed to assess any potential hypotensive effect of PM101 (50 mg/ml) on the administration of the loading dose (150 mg) as an undiluted bolus push. This was a randomized, double-blind, placebo- and active-controlled study in healthy human subjects receiving placebo (5% dextrose in water, n = 112) or PM101 (bolus push, n = 112). The primary end point was the noninferiority assessment of placebo versus PM101 for change in systolic blood pressure. For comparison, the standard loading dose of AIV (150 mg) was infused at 1.5 mg/ml over 10 minutes, and a rapid loading dose of AIV (150 mg) was infused undiluted (50 mg/ml) over 15 seconds. PM101 was noninferior to placebo, with changes from baseline systolic blood pressure for placebo and PM101 of -4.25 +/- 4.2 and -4.83 +/- 5.0 mm Hg, respectively. Neither regimen of AIV altered systolic blood pressure compared to placebo. Transient and significant increases in heart rate were observed in both AIV groups and with PM101 but not placebo. In conclusion, the results of this study demonstrate that PM101 is devoid of hypotension in healthy human subjects. The absence of a hypotensive effect of AIV in this population suggests that further evaluation is needed in a patient population with cardiac disease.

Bioequivalence of 2 intravenous amiodarone formulations in healthy participants.

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight participants were enrolled in this randomized, double-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The amiodarone plasma concentration-time curve observed with both formulations was virtually identical, as was the 72-hour area under the curve (AUC0-72). Similar equivalence was seen for desethylamiodarone, the active metabolite of amiodarone. The geometric ratios of the AUC0-72 for amiodarone and desethylamiodarone were 1.03 (95% confidence interval [CI], 1.00-1.06) and 1.01 (0.99-1.03), respectively. Similar geometric ratios and CIs were found for maximum plasma concentration (Cmax) and for AUC extrapolated to infinity (AUC0-infinity). Because the ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to PM101 were identified.

Single- and multiple-dose pharmacokinetic and dose-proportionality study of oxymorphone immediate-release tablets.

INTRODUCTION: Oxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic mu-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers. STUDY DESIGN: A randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women. METHODS: A single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state. RESULTS: Twenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC(infinity)] 4.5, 9.1 and 20.1 microg . h/L, respectively) and maximum plasma concentration ([C(max)] 1.1, 1.9 and 4.4 microg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and C(max) of oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median t(max) (time to reach C(max)) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t(1/2)) was approximately 7.3-9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted. DISCUSSION: Because successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.

Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and dose-proportionality of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended release (ER) under both single-dose and steady-state conditions. DESIGN: Randomized, three-period, four-sequence, crossover study. SETTING: Bioavailability clinic. SUBJECTS: Twenty-four healthy adult volunteers. INTERVENTION: Each subject received three of the four possible doses. The three 8-day administration periods were separated by a 7-day washout. Plasma was collected for up to 48 hours after a single dose on day 1 and during a 12-hour dosage interval at steady state. Naltrexone was administered to reduce opioid-related adverse effects. MEASUREMENTS AND MAIN RESULTS: Twenty-three subjects completed at least one study period. Dose-proportionality and linearity were confirmed after single doses (mean oxymorphone ER area under the concentration versus time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses, respectively) and at steady state (mean oxymorphone ER AUC 5.60, 9.77, 19.3, and 37.0 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses every 12 hrs, respectively). Similar results were found for maximum plasma concentration. Metabolite (6-hydroxyoxymorphone and oxymorphone-3-glucuronide) plasma levels also increased in a linear fashion after single-dose administration and at steady state. CONCLUSION: The pharmacokinetic profile of oxymorphone ER demonstrates linearity and dose-proportionality under single-dose and steady-state conditions for the parent compound and its metabolites for doses of 5-40 mg.