FORMULATION OPTIMIZATION AND EVALUATION OF FLURBIPROFEN EMULGEL

Objective: The objective of the present study was to formulate flurbiprofen (FLB) emulgel, evaluation of the formulations and the selection of an optimized formulation through in vitro drug release and drug content studies. Flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID) requiring frequent administration and its chronic intake can lead to systemic side effects like gastric irritation and GI bleeding. The development of a dermal drug delivery system can overcome these side effects. Methods: The emulgel formulations were produced using different combinations of oil and emulsifying agents. Carbopol 940 was used as a gelling agent. The prepared emulgels were evaluated for general appearance, pH, spreadability, extrudability, drug content, in vitro drug release, average globule size and viscosity. Results: Optimized formulation F7 showed a better in vitro drug release compared to the marketed gel preparation. The stability study for the optimized formulation was carried out at 25 °C/60 % RH for 3 mo and the emulgel was found to be stable concerning the physical appearance, pH and drug content. Conclusion: The study revolved around the formulation of emulgel containing Flurbiprofen for dermal delivery of the drug. Emulgel was formulated with the purpose to enhance the permeation of poorly water-soluble drug FLB. The study concluded that the optimized emulgel containing FLB exhibited better in vitro drug release profile compared to the marketed formulation

The mean-squared displacement of a molecule moving in a glassy system

The mean-squared displacement (MSD) of a hard sphere and of a dumbbell molecule consisting of two fused hard spheres immersed in a dense hard-sphere system is calculated within the mode-coupling theory for ideal liquid-glass transitions. It is proven that the velocity correlator, which is the second time derivative of the MSD, is the negative of a completely monotone function for times within the structural-relaxation regime. The MSD is found to exhibit a large time interval for structural relaxation prior to the onset of the $\alpha$-process which cannot be described by the asymptotic formulas for the mode-coupling-theory-bifurcation dynamics. The $\alpha$-process for molecules with a large elongation is shown to exhibit an anomalously wide cross-over interval between the end of the von-Schweidler decay and the beginning of normal diffusion. The diffusivity of the molecule is predicted to vary non-monotonically as function of its elongation.Comment: 18 pages, 12 figures, Phys. Rev. E, in prin

Test of mode coupling theory for a supercooled liquid of diatomic molecules.I. Translational degrees of freedom

A molecular dynamics simulation is performed for a supercooled liquid of rigid diatomic molecules. The time-dependent self and collective density correlators of the molecular centers of mass are determined and compared with the predictions of the ideal mode coupling theory (MCT) for simple liquids. This is done in real as well as in momentum space. One of the main results is the existence of a unique transition temperature T_c, where the dynamics crosses over from an ergodic to a quasi-nonergodic behavior. The value for T_c agrees with that found earlier for the orientational dynamics within the error bars. In the beta- regime of MCT the factorization of space- and time dependence is satisfactorily fulfilled for both types of correlations. The first scaling law of ideal MCT holds in the von Schweidler regime, only, since the validity of the critical law can not be confirmed, due to a strong interference with the microscopic dynamics. In this first scaling regime a consistent description within ideal MCT emerges only, if the next order correction to the asymptotic law is taken into account. This correction is almost negligible for q=q_max, the position of the main peak in the static structure factor S(q), but becomes important for q=q_min, the position of its first minimum. The second scaling law, i.e. the time-temperature superposition principle, holds reasonably well for the self and collective density correlators and different values for q. The alpha-relaxation times tau_q^(s) and tau_q follow a power law in T-T_c over 2 -- 3 decades. The corresponding exponent gamma is weakly q-dependent and is around 2.55. This value is in agreement with the one predicted by MCT from the value of the von Schweidler exponent but at variance with the corresponding exponent gammaComment: 14 pages of RevTex, 19 figure

Molecular dynamics simulation of the fragile glass former ortho-terphenyl: a flexible molecule model

We present a realistic model of the fragile glass former orthoterphenyl and the results of extensive molecular dynamics simulations in which we investigated its basic static and dynamic properties. In this model the internal molecular interactions between the three rigid phenyl rings are described by a set of force constants, including harmonic and anharmonic terms; the interactions among different molecules are described by Lennard-Jones site-site potentials. Self-diffusion properties are discussed in detail together with the temperature and momentum dependencies of the self-intermediate scattering function. The simulation data are compared with existing experimental results and with the main predictions of the Mode Coupling Theory.Comment: 20 pages and 28 postscript figure

Fast relaxation in a fragile liquid under pressure

The incoherent dynamic structure factor of ortho-terphenyl has been measured by neutron time-of-flight and backscattering technique in the pressure range from 0.1 MPa to 240 MPa for temperatures between 301 K and 335 K. Tagged-particle correlations in the compressed liquid decay in two steps. The alpha-relaxation lineshape is independent of pressure, and the relaxation time proportional to viscosity. A kink in the amplitude f_Q(P) reveals the onset of beta relaxation. The beta-relaxation regime can be described by the mode-coupling scaling function; amplitudes and time scales allow a consistent determination of the critical pressure P_c(T). alpha and beta relaxation depend in the same way on the thermodynamic state; close to the mode-coupling cross-over, this dependence can be parametrised by an effective coupling Gamma ~ n*T**{-1/4}.Comment: 4 Pages of RevTeX, 4 figures (submitted to Physical Review Letters

Growth of the digital footprint of the society of critical care medicine annual congress: 2014-2020

Objectives: Since 2014, the Society of Critical Care Medicine has encouraged “live-tweeting” through the use of specific hashtags at each annual Critical Care Congress. We describe how the digital footprint of the Society of Critical Care Medicine Congress on Twitter has evolved at a time when social media use at conferences is becoming increasingly popular. Design: We used Symplur Signals (Symplur LLC, Pasadena, CA) to track all tweets containing the Society of Critical Care Medicine Congress hashtag for each annual meeting between 2014 and 2020. We collected data on the number of tweets, tweet characteristics, and impressions (i.e., potential views) for each year and data on the characteristics of the top 100 most actively tweeting users of that Congress

Statistical Mechanics of Glass Formation in Molecular Liquids with OTP as an Example

We extend our statistical mechanical theory of the glass transition from examples consisting of point particles to molecular liquids with internal degrees of freedom. As before, the fundamental assertion is that super-cooled liquids are ergodic, although becoming very viscous at lower temperatures, and are therefore describable in principle by statistical mechanics. The theory is based on analyzing the local neighborhoods of each molecule, and a statistical mechanical weight is assigned to every possible local organization. This results in an approximate theory that is in very good agreement with simulations regarding both thermodynamical and dynamical properties

Dynamics of the rotational degrees of freedom in a supercooled liquid of diatomic molecules

Using molecular dynamics computer simulations, we investigate the dynamics of the rotational degrees of freedom in a supercooled system composed of rigid, diatomic molecules. The interaction between the molecules is given by the sum of interaction-site potentials of the Lennard-Jones type. In agreement with mode-coupling theory (MCT), we find that the relaxation times of the orientational time correlation functions C_1^(s), C_2^(s) and C_1 show at low temperatures a power-law with the same critical temperature T_c, and which is also identical to the critical temperature for the translational degrees of freedom. In contrast to MCT we find, however, that for these correlators the time-temperature superposition principle does not hold well and that also the critical exponent gamma depends on the correlator. We also study the temperature dependence of the rotational diffusion constant D_r and demonstrate that at high temperatures D_r is proportional to the translational diffusion constant D and that when the system starts to become supercooled the former shows an Arrhenius behavior whereas the latter exhibits a power-law dependence. We discuss the origin for the difference in the temperature dependence of D (or the relaxation times of C_l^(s) and D_r. Finally we present results which show that at low temperatures 180 degree flips of the molecule are an important component of the relaxation dynamics for the orientational degrees of freedom.Comment: 17 pages of RevTex, 12 figure

Comparing the digital footprint of pulmonary and critical care conferences on Twitter

Background: Pulmonary and critical care societies, including the American Thoracic Society, the American College of Chest Physicians, and the Society of Critical Care Medicine have large memberships that gather at academic conference events, attracting thousands of attendees. Objective: With the growth of social media use among pulmonary and critical care clinicians, our goal was to examine the Twitter presence and digital footprint of these three major medical society conferences. Methods: We used Symplur Signals (Symplur, LLC) to track the tweets and most active participants of the 2017–2019 annual conferences of American Thoracic Society, American College of Chest Physicians, and the Society of Critical Care Medicine. Attendance records of participants were obtained from each society. Results: During the study period, there was growth in the number of tweets, participants, and impressions for all three society conferences. Across all conferences, the amount of original content generated was less than the retweets, which comprised 50–72% of all tweets. Individuals physically attending each conference were more likely to post original content than those not in attendance (53–68% vs. 32–47%). For each society and at each meeting, clinicians made up the largest group of participants (44–60%), and most (59–82%) were physicians. A small cohort of participants was responsible for a large share of the tweets, with more than half of the participants at each conference for each society tweeting only once and only between 5–8% of participants tweeting more than 10 times. Seventy-eight individuals tweeted more than 100 times at one or more of the conferences. There was significant overlap in this group, with 32 of these individual participants tweeting more than 100 times at two or more of these conferences. Conclusion: Growth in conference digital footprints is largely due to increased activity by a small group of prolific participants that attend conferences by multiple academic societies. Original content makes up the smallest proportion of posts, suggesting that amplification of content is more prevalent than posting of original content. In a postpandemic environment, engagement of users producing original content may be even more important for medical societies

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I–V and of grade III–V immune-related adverse events (irAEs) was 37% and 7%, respectively. Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over (‘crossover’). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 (‘rechallenge’). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7–15.2) and the 3-year PFS rate was 32% (95% CI 25–40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48–83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6–NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I–IV irAE and 11 (6%) had a grade III–IV irAE. Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged