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In addition to the proinflammatory state, cytokine production, and cell death, SARS-CoV-2 infection is also associated with oxidative stress as demonstrated by increase in reactive oxygen species (ROS) levels and an alteration of antioxidant defense during the infection. Proinflammatory cytokines and chemokines play an important role in respiratory infections caused by viruses including SARS-CoV-2 by activation of the adaptive immune response. In case when the response is not controlled, it can lead to lung tissue involvement in the course of acute respiratory distress syndrome (ARDS) or can result in multiple organ failure. Oxidative stress markers show good correlation with several cytokines, which can be measured at the beginning of the disease in a primary care setting to predict the course of COVID-19.

BACKGROUND: COVID-19 is characterized by the presence of oxidative stress. Vitamin D status has been reviewed as one of the factors that may affect disease severity. The aim of this study was to assess the relationship between serum vitamin D levels, oxidative stress markers and disease severity in hospitalized COVID-19 patients. METHODS: Vitamin D levels were measured in 33 patients with COVID-19. The total antioxidant power and plasma peroxides were determined in serum. RESULTS: Severe COVID-19 patients have lower vitamin D levels (18.39 ± 2.29 ng/mL vs. 28.47 ± 3.05 ng/mL, p < .05) and higher oxidative stress compared to the moderate group. When divided according to serum vitamin D levels, significantly higher values of LDH (604.8 ± 76.98 IU/mL vs. 261.57 ± 47.33 IU/mL) and D-dimer (5978 ± 2028ng/mL vs. 977.7 ± 172 ng/mL) were obtained in the group with vitamin D below 30 ng/mL, followed with significantly higher levels of plasma peroxides (d-ROMs: 414.9 ± 15.82 U.Carr vs. 352.4 ± 18.77 U.Carr; p < .05) and oxidative stress index (OSI: 92.25 ± 6.60 vs. 51.89 ± 6.45; p < .001). CONCLUSION: The presented data provide a justification to consider vitamin D as an important factor that could ameliorate disease severity through its anti-inflammatory and antioxidant effects.

Herein synchronous occurrence of Hodgkin lymphoma and secondary myelodysplastic syndrome in a 60 year old male patient with small cell lung cancer treated with combined chemotherapy (carboplatin and paclitaxel) and radiotherapy is presented. The objective of this report is to stress the importance of documenting and monitoring adverse drug reactions that arise from chemotherapy. After four years of treatment with the combined chemotherapy, the patient presented inguinal lymphadenopathy and enlarged lymph nodes and histopathology rapport was suggestive for plasmacytoid variant of Castleman disease. Three years later, biopsy of lymph node was performed and diagnosis of Hodgkin lymphoma – mixed cellularity has been established. Molecular analyses revealed presence of dominant monoclonal population of the immunoglobulin genes in the oligo/monoclonal background. Bone marrow biopsy findings suggested secondary myelodysplasia and revealed signs of hematopoietic cells dismaturation with signs of megaloblastic maturation of the erytropoetic lineage, appearance of ALIP (abnormal localization of immature precursors) in the myeloid lineage and dysplastic megakaryocytes. In addition, an increased level of polyclonal plasmacytes (lambda vs kappa was 60%:40%) was found. Hodgkin lymphoma and MDS occurring after 4 years of carboplatin/paclitaxel therapy might be contributed to the accumulation of alkylator-related DNA damage. This emphasize the need of outlining a monitoring plan regarding development of secondary leukemia and other malignant hematological proliferations should be outlined in the protocols.

The aim of the present study was to demonstrate the application of an automated high-throughput (HT) dissolution method as a useful screening tool for characterization of controlled release pellets in the formulation development phase. Five controlled release pellet formulations with drug substances exhibiting high or low solubility were chosen to investigate the correlation of the automated HT dissolution method with the conventional dissolution testing. Overall, excellent correlations (R(2 )>( )0.96) between the HT and the conventional dissolution method were obtained. In one case the initial unsatisfactory correlation (R(2 )=( )0.84) and poor method agreement (SD = 12.5) was improved by optimizing the HT dissolution method with design of experiment approach. Here in comparison to initial experimental HT dissolution settings, increased amount of pellets (25% of the capsule filling mass), lower temperature (22 °C) and no shaking resulted in significantly better correlation (R(2 )=( )0.97) and method agreement (SD = 5.3). These results show that such optimization is valuable for the development of HT dissolution methods. In conclusion, the high correlation of dissolution profiles obtained from the conventional and the automated HT dissolution method combined with low within-sample and measurement system variability, justifies the utilization of the automated HT dissolution method during development phase of controlled release pellets.

Considering the confusing biodistribution data through the literature and few reported alerts as well as our preliminary biodistribution results, we decided to evaluate the interaction and interference of the commonly present (99m) Tc (technetium-99m)-stannic oxide colloid during the direct stannous chloride (99m) Tc-labeling procedure and to assess its influence on the biodistribution pattern of amphiphilic poly(lactic-co-glycolic acid) nanoparticles. In order to confirm our thesis, beside stannous chloride, we employed two different reducing agents that don't form colloidal particles. The use of sodium borohydride was previously reported in the literature, whereas sodium dithionite was adapted for the first time in the (99m) Tc direct labeling procedure for nanoparticles. The results in our paper clearly differentiate among samples with and without colloidal impurities originating from the labeling procedure with a logical follow up of the radiochemical, physicochemical evaluation, and biodistribution studies clarifying previously reported data on stannic oxide colloidal interference. (99m) Tc-nanoparticle complex labeled with sodium dithionite as reducing agent illustrated appropriate labeling efficacy, stability, and potential for further use in biodistribution studies thus providing solution for the problem of low-complex stability when sodium borohydride is used and colloidal stannic oxide interference for stannous chloride procedure.

The aim of this study was to develop a sirolimus (BCS class II drug substance) solid oral dosage form containing a precipitation inhibitor, which would result in an improved sirolimus absorption in humans compared to the formulation containing nanosized sirolimus without a precipitation inhibitor, i.e., Rapamune. The selection of the precipitation inhibitor was based on the results of a screening campaign that identified two "hit" excipients: HPMC 603 (i.e., Pharmacoat 603) and Poloxamer 407. However, in a confirmatory precipitation inhibitor study using biorelevant media (Fa/FeSSIF) HPMC 603 more effectively inhibited sirolimus precipitation than Poloxamer 407. In the PAMPA assay, HPMC 603, but not Poloxamer 407, significantly increased the flux of the sirolimus across the membrane lipid layer. Additionally, a differential scanning calorimetry (DSC) and an infrared (IR) spectroscopy study revealed that interactions between the sirolimus and HPMC 603 were developed that could lead to the observed precipitation inhibition effect. Based on the above data, two formulations with HPMC 603-coated sirolimus particles were developed, namely, formulation A (d (0.5) = 0.21 μm) and formulation B (d (0.5) = 1.7 μm). A human pharmacokinetic study outlined that significantly higher AUC and Cmax were obtained for formulations A and B in comparison to Rapamune. This result could be attributed to the HPMC 603 (Pharmacoat 603) mediated sirolimus precipitation inhibition resulting in improved sirolimus absorption from the gastrointestinal tract in humans.

In this study, hybrid silica xerogel particles were developed as carriers of budesonide (BDS) for efficient local treatment of inflammatory bowel diseases (IBD). Organically modified silica particles (ORMOSILs) were prepared by co-condensation of 3-aminopropyltriethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) by an ambient temperature acid catalysed sol-gel process followed by spray-drying. Formulation for preparation of BDS-loaded particles was optimized and their physicochemical parameters and drug release profiles were evaluated in vitro. Optimal formulation had a small particle size (mean diameter of 1.45±0.02μm) with unimodal narrow size distribution and high encapsulation efficiency (98.0 ± 1.85%). Due to the positive surface charge originated from amino group of APTES, ORMOSILs showed excessive mucoadhesiveness in comparison to native TEOS particles. The drug release decreased with increasing pH from 2.0 to 7.4. In order to avoid undesirable erroneous performance in the upper GI tract, particles were additionally coated with Eudragit(®) FS 30D, as a barrier to the drug release at pH range from 2.0 to 7.0. After Eudragit(®) FS 30D coating, the release of BDS in acidic media was sustained, while no significant differences in drug release were observed at pH 7.4. In conclusion, pH-responsive ORMOSILs showed great potential for efficient BDS delivery to the colon region.

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.

The process of molecular self-assembly plays a crucial role in formulation of polymeric nanoparticulated drug delivery carriers as it creates the possibility for enhanced drug encapsulation and carrier surface engineering. This study aimed to develop a novel self-assembled polymeric micelles for targeted delivery in tumor cells in order to overcome not only various drawbacks of 7-ethyl-10-hydroxy camptothecin (SN-38) but also various reported limitations of other drug delivery systems, especially low drug loading and premature release. Custom synthesized amphiphilic triblock copolymer poly(acrylic acid)–poly(ɛ-caprolactone)–poly(acrylic acid) (PAA13–PCL35–PAA13) was used to prepare kinetically stable micelles by nanoprecipitation and modified nanoprecipitation procedure. Core-shell micelles with diameter of 120–140 nm, negative zeta potential and satisfactory drug loading were produced. The prepared formulations were stable in pH range of 3–12 and in media with NaCl concentration 2 design identified that the process temperature as well as the type of organic solvent has influence upon the efficacy of encapsulation, particle size, dissolution rate and burst release. Fourier transform infrared and differential scanning calorimetry analyses confirmed the entrapment of the active substance into the micelles. The kinetic analysis of dissolution studies revealed that the main mechanism of drug release from the prepared formulations is Fickian diffusion. Growth inhibition studies as well as DNA fragmentation assay performed on SW-480 cell lines clearly demonstrated increased growth inhibition effect and presence of fragmented DNA in cells treated with loaded micelles compared to SN-38 solution. Altogether, these results point out to potential biomedical and clinical application of PAA–PCL–PAA systems in the future.

The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors.

Considering the confusing biodistribution data through the literature and few reported alerts as well as our preliminary biodistribution results, we decided to evaluate the interaction and interference of the commonly present (99m) Tc (technetium-99m)-stannic oxide colloid during the direct stannous chloride (99m) Tc-labeling procedure and to assess its influence on the biodistribution pattern of amphiphilic poly(lactic-co-glycolic acid) nanoparticles. In order to confirm our thesis, beside stannous chloride, we employed two different reducing agents that don't form colloidal particles. The use of sodium borohydride was previously reported in the literature, whereas sodium dithionite was adapted for the first time in the (99m) Tc direct labeling procedure for nanoparticles. The results in our paper clearly differentiate among samples with and without colloidal impurities originating from the labeling procedure with a logical follow up of the radiochemical, physicochemical evaluation, and biodistribution studies clarifying previously reported data on stannic oxide colloidal interference. (99m) Tc-nanoparticle complex labeled with sodium dithionite as reducing agent illustrated appropriate labeling efficacy, stability, and potential for further use in biodistribution studies thus providing solution for the problem of low-complex stability when sodium borohydride is used and colloidal stannic oxide interference for stannous chloride procedure.

The objective of this study was to evaluate the suitability and acceptance criteria of isolated rat jejunum model for Biopharmaceutics Classification System (BCS)—permeability classification. The evaluation followed recommended procedures including investigation of tissue integrity by applying damage triggers (nitrogen gassing, elevated temperature, azide addition), characterization of transporter functionality, and expression and development of correlation between rats' apparent permeability coefficient ( P app ) versus humans' and versus oral fraction absorbed ( f a ) in humans. Firstly, damage triggers caused a decrease in transepithelial resistance and potential difference and increase in lucifer yellow (LY) and fluorescein isothiocyanate (FITC)–dextran P app . However, only FITC–dextran P app 's increase was considered significant in all treatment groups, making FITC–dextran a better indicator of jejunum integrity than LY. Secondly, the expression level of selected intestinal transporters highly correlated between rat and human and functionality of P-glycoprotein was confirmed. P app of investigated drugs correlated with human f a ( R 2 = 0.85, n = 20) and with human permeability coefficients ( R 2 = 0.86, n = 13). Utility of described model for BCS classification was shown on levetiracetam, where significantly higher permeability of levetiracetam as compared with internal standard metoprolol was determined ( t -test, p = 0.005). In conclusion, isolated rat jejunum model is a useful tool not only for mechanistic investigation, but also for permeability classification according to BCS and consequently for BCS-based biowaiver procedures.