Andrzej Grzybowski

The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults

The reactive oxygen species (ROS) form under normal physiological conditions and may have both beneficial and harmful role. We search the literature and current knowledge in the aspect of ROS participation in the pathogenesis of anterior and posterior eye segment diseases in adults. ROS take part in the pathogenesis of keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, stimulating apoptosis of corneal cells. ROS play a role in the pathogenesis of glaucoma stimulating apoptotic and inflammatory pathways on the level of the trabecular meshwork and promoting retinal ganglion cells apoptosis and glial dysfunction in the posterior eye segment. ROS play a role in the pathogenesis of Lebers hereditary optic neuropathy and traumatic optic neuropathy. ROS induce apoptosis of human lens epithelial cells. ROS promote apoptosis of vascular and neuronal cells and stimulate inflammation and pathological angiogenesis in the course of diabetic retinopathy. ROS are associated with the pathophysiological parainflammation and autophagy process in the course of the age-related macular degeneration.

Molecular Dynamics and Physical Stability of Amorphous Anti-Inflammatory Drug: Celecoxib

By using dielectric spectroscopy we analyzed the relation between molecular mobility and tendency of the amorphous celecoxib to recrystallize. We found that celecoxib is kinetically a fragile glassformer, contrary to the conclusion reached by others from thermodynamic fragility. The possible correlation of the large tendency of celecoxib to crystallize with various molecular motions have been investigated. Our study shows that the structural relaxation seems to be responsible for devitrification of celecoxib if stored at room temperature ∼293 K. Notwithstanding, the crystallization can be considered to ultimately be affected by the β-process (JG-relaxation) because it is the precursor of the structural α-relaxation.

Enhancement of amorphous celecoxib stability by mixing it with octaacetylmaltose: the molecular dynamics study.

In this paper, we present a novel way of stabilization of amorphous celecoxib (CEL) against recrystallization by preparing binary amorphous celecoxib-octaacetylmaltose (CEL-acMAL) systems by quench-cooling of the molten phase. As far as we know this is the first application of carbohydrate derivatives with acetate groups to enhance the stability of an amorphous drug. We found that CEL in the amorphous mixture with acMAL is characterized by a much better solubility than pure CEL. We report very promising results of the long-term measurements of stability of the CEL-acMAL binary amorphous system with small amount of stabilizer during its storage at room temperature. Moreover, we examined the effect of adding acMAL on molecular dynamics of CEL in the wide temperature range in both the supercooled liquid and glassy states. We found that the molecular mobility of the mixture of CEL with 10 wt % acMAL in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better stability of the amorphous binary system. By dielectric measurements and theoretical calculations within the framework of density functional theory (DFT), we studied the role of acMAL in enhancing the stability of amorphous CEL in mixtures and postulated which interactions between CEL and acMAL molecules can be responsible for preventing devitrification.

Relaxation Dynamics and Crystallization Study of Sildenafil in the Liquid and Glassy States

In this paper, the physical stability and molecular dynamics of amorphous sildenafil are investigated in both the liquid and glassy states. We have established that the amorphous sildenafil is resistant to recrystallization at temperatures below the glass transition temperature Tg during the experimental period of its storage (i.e., above 6 months), however, it easily undergoes cold crystallization at T > Tg. To determine the crystallization mechanism, the isothermal and non-isothermal studies of the cold crystallization kinetics of the drug are performed by using the broadband dielectric spectroscopy (BDS) and the differential scanning calorimetry (DSC), respectively. The cold crystallization mechanism has been found to be similar in both the isothermal and non-isothermal cases. This mechanism has been analyzed from the point of view of the molecular mobility of sildenafil investigated in the supercooled liquid and glassy states by using the BDS measurements in the wide temperature range. This analysis has been enriched with a new approach based on a recently reported measure of dynamic heterogeneity given by a four-point dynamic susceptibility function. No tendency to recrystallization of glassy sildenafil at T < Tg is also discussed in relation to molecular dynamics of sildenafil in the glassy state. The relatively small molecular mobility reflected in one secondary relaxation as well as the predicted large time scale of structural relaxation of glassy sildenafil suggests that amorphous sildenafil should not recrystallize during its long-term storage at room temperature.

Cycloplegic refraction is the gold standard for epidemiological studies

Many studies on children have shown that lack of cycloplegia is associated with slight overestimation of myopia and marked errors in estimates of the prevalence of emmetropia and hyperopia. Non‐cycloplegic refraction is particularly problematic for studies of associations with risk factors. The consensus around the importance of cycloplegia in children left undefined at what age, if any, cycloplegia became unnecessary. It was often implicitly assumed that cycloplegia is not necessary beyond childhood or early adulthood, and thus, the protocol for the classical studies of refraction in older adults did not include cycloplegia. Now that population studies of refractive error are beginning to fill the gap between schoolchildren and older adults, whether cycloplegia is required for measuring refractive error in this age range, needs to be defined. Data from the Tehran Eye Study show that, without cycloplegia, there are errors in the estimation of myopia, emmetropia and hyperopia in the age range 20–50, just as in children. Similar results have been reported in an analysis of data from the Beaver Dam Offspring Eye Study. If the only important outcome measure of a particular study is the prevalence of myopia, then cycloplegia may not be crucial in some cases. But, without cycloplegia, measurements of other refractive categories as well as spherical equivalent are unreliable. In summary, the current evidence suggests that cycloplegic refraction should be considered as the gold standard for epidemiological studies of refraction, not only in children, but in adults up to the age of 50.

Age-Related Macular Degeneration in the Aspect of Chronic Low-Grade Inflammation (Pathophysiological ParaInflammation)

The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages).

High pressure study of molecular dynamics of protic ionic liquid lidocaine hydrochloride

In this paper, we investigate the effect of pressure on the molecular dynamics of protic ionic liquid lidocaine hydrochloride, a commonly used pharmaceutical, by means of dielectric spectroscopy and pressure-temperature-volume methods. We observed that near T(g) the pressure dependence of conductivity relaxation times reveals a peculiar behavior, which can be treated as a manifestation of decoupling between ion migration and structural relaxation times. Moreover, we discuss the validity of thermodynamic scaling in lidocaine HCl. We also employed the temperature-volume Avramov model to determine the value of pressure coefficient of glass transition temperature, dT(g)/dP|(P = 0.1). Finally, we investigate the role of thermal and density fluctuations in controlling of molecular dynamics of the examined compound.

Consequences of an equation of state in the thermodynamic scaling regime.

An equation of state following from the generalized Lennard-Jones potential has been successfully applied to describe isothermal volumetric data for several glass-forming liquids on the assumption of the thermodynamic scaling validity. The scaling exponents gamma evaluated from the fitting procedure for each tested material have turned out at least 2 times larger than those earlier found from relaxation data. The discrepancy indicates that the appealing idea of thermodynamic scaling, which has been recently intensively explored, requires more efforts to find a satisfying theoretical grounds for it.

Scaling of volumetric data in model systems based on the Lennard-Jones potential.

The crucial problem for better understanding the nature of glass transition and related relaxation phenomena is to find proper interrelations between the molecular dynamics and thermodynamics of viscous systems. To make progress towards this goal the recently observed density scaling of viscous liquid dynamics has been very intensively and successfully studied in the past few years. However, previous attempts at related scaling of volumetric data yielded results inconsistent with those found from the density scaling of molecular dynamics. In this paper, we show that volumetric data obtained from simulations in simple molecular models based on the Lennard-Jones (LJ) potential, such as the Kob-Andersen binary LJ liquid, its repulsive inverse power-law version, and the Lewis-Wahnström o-terphenyl model, can be scaled by using the same value of the exponent, which scales dynamic quantities and is directly related to the exponent of the repulsive inverse power law that underlies short-range approximations of the LJ potential.

Intracameral Antibiotics and Cataract Surgery: Endophthalmitis Rates, Costs, and Stewardship.

Acute-onset postoperative endophthalmitis is a rare but vision-threatening complication of cataract surgery. The incidence rate varies substantially in the literature but is generally reported in the range of 0.03% to 0.2%. In the current issue of Ophthalmology, Creuzot-Garcher et al report a retrospective series of 6 371 242 phacoemulsification surgeries in which the rate of endophthalmitis declined from 0.145% to 0.053% over a 10-year period (see page XXX). During this timeframe, the use of intracameral antibiotics increased from 0.60% to 80.03%, and the investigators concluded that the intracameral antibiotics were responsible for these outcomes. These results are intriguing and illustrate the power of “Big