Oral cyclosporine a nanosuspension for improved immunosuppressive efficacy: In vivo cytokine profiling in rats.

Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. A Design of Experiment approach

A historical note on the development of zimelidine, the first selective serotonin reuptake inhibitor

Lutein is a kind of natural carotenoids possessing many pharmacological effects. The application of lutein was limited mainly due to its low oral bioavailability caused by poor aqueous solubility. Nanocrystal formulation of lutein was developed to improve the oral bioavailability in this study. The nanosuspension was prepared by the anti-solvent precipitation-ultrasonication method and optimized by Box–Behnken design, followed by freeze-drying to obtain lutein nanocrystals. The nanocrystals were characterized on their physical properties, in vitro dissolution and in vivo absorption performance. Lutein nanocrystals showed as tiny spheres with an average particle size of 110.7 nm. The result of diffractograms indicated that the percent crystallinity of lutein was 89.4% in coarse powder and then declined in nanocrystal formulation. The saturated solubility of lutein in water increased from 7.3 μg/ml for coarse powder up to 215.7 μg/ml for lutein nanocrystals. The dissolution rate of lutein nanocrystals was significantly higher than that of coarse powder or the physical mixture. The Cmax and AUC0–24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension, respectively. These results indicated that the nanocrystal formulation could significantly enhance the dissolution and absorption of lutein and might be a promising approach for improving its oral bioavailability.

Evaluation of improved oral bioavailability of ritonavir nanosuspension

Optimization and in vitro evaluation of ziprasidone nanosuspensions produced by a top-down approach

Dermal flurbiprofen nanosuspensions: Optimization with design of experiment approach and in vitro evaluation

Andrographolide (ADG) is a diterpenoid isolated from Andrographis paniculata with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box–Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability (Papp) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (P<0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure with significant enhancements in Cmax and area under the curve of plasma concentration versus time from zero to the last sampling time (AUC0−t) (P<0.01). An evaluation of the anti-inflammatory effect on Carr-induced paw edema demonstrated that the ADG-NS were more effective in reducing the rate of paw swelling, producing a greater increase in the serum levels of nitric oxide (NO), Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) (P<0.01) and an increase in superoxide dismutase activity (P<0.05) compared to the ADG coarse powder. This study indicated that nanosuspensions could act as an effective delivery device for ADG to enhance its oral bioavailability and biological efficacy.

Objective: To evaluate the impact of a self-nanoemulsifying drug delivery system (SNEDDS) incorporated into liquisolid tablets (LSTs) and the natural bioenhancer piperine (Pip) on the bioavailability, immunosuppressive efficacy, and toxicity of tacrolimus (Tac). Methods: An optimized Tac-SNEDDS was developed and formulated into four LST compositions using various carriers and coatings (Neusilin®-Avicel®/FujiSil®-fumed silica). The optimal Tac-LST formulation was selected based on drug content and tested in Wistar rats. Bioavailability was assessed using the limited area under the curve (AUC₀₋₆), while immunosuppressive efficacy was evaluated through IL-2 levels. Renal histology and serum cystatin C levels were analyzed to assess potential nephrotoxicity. Results: Among the four Tac-LST formulations, LST-4 (Avicel®/FujiSil®) exhibited the highest drug content and was chosen for in vivo studies. Co-administration of Pip, LSTs, and their combination significantly improved Tac bioavailability without compromising immunosuppressive activity. Pip co-administration demonstrated superior IL-2 inhibition compared to Tac alone or Tac-LSTs. Additionally, Pip reduced Tac-induced increases in serum cystatin C levels and mitigated renal histological damage, indicating a nephroprotective effect. The combination of Pip and Tac-LSTs provided the most stable absorption profile with minimal AUC fluctuations, suggesting a more predictable pharmacokinetic profile. Conclusion: Pip and LST formulations significantly enhance Tac bioavailability while maintaining its immunosuppressive efficacy. Moreover, Pip exhibits a protective effect against Tac-induced nephrotoxicity. The combination of Pip and Tac-LSTs offers a stable pharmacokinetic profile, potentially improving therapeutic outcomes by maintaining consistent drug levels.

Background. One of the most prominent features of secondary edematous breast cancer (SEBC), which is the most malignant form of this type of cancer, is severity of chronic inflammation that is important for pathogenesis and progression of the disease. As of now, there is evidence of association of carcinogenesis and inflammation. The transcription factor (NF-kB) and pro-inflammatory cytokines play a pivotal role in both inflammation and carcinogenesis. The regulation of NF-kB signal pathways is impaired in a lot of malignant diseases, including breast cancer (BC). Thus, the study of the content of pro-inflammatory cytokines and NF-kB is of high priority, as it can provide valuable information about the course of the tumor process. However, there are few research papers that deal with association of cytokine profile and NF-kB in breast tumors. Purpose – is to study the content of NF-kB-р105 and pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with secondary edematous breast cancer. Materials and Methods. 87 patients (42 with SEBC, 45 with BC) were examined prior to treatment. The age of 42 patients with T4bN0-3M0 SEBC ranged from 34 to 71 years (median 53.1). The ductal cancer was found in 30 patients (71.43%), the lobular cancer – in 12 patients (28.57%). The tumor of more than 5 cm was detected in 20 individuals (47.6%), the tumor of less than 5 cm – in 22 individuals (52.4%). The comparison group consisted of 45 patients with BC, with their age ranging from 30 to 67 years (median 52.3). They had T3-4N1-3M0 non-edematous locally advanced BC. The tumor of more than 5 cm was detected in 12 patients (26.7%), the tumor of less than 5 cm – in 33 patients (73.3%). The ductal cancer was diagnosed in 33 patients (73.3%), the lobular cancer – in 12 patients (26.7%). The control group consisted of 10 patients with fibroadenomas. The content of cytokines (IL-1B, IL-2, IL-6, IL-8, TNFα) in the blood serum of patients was measured using the ELISA assay and CJSC «Vektor-Best» standard assay kits. The content of NF-kB1 subunit (р105 → р50) was measured using the ELISA assay and the Human NFkB – p105 (Nuclear factor NF-kappa-B p 105 subunit) ELISA Kit. The measurement was performed using the Immunochem-2100 American semi-automatic immunoassay analyzer. Results. It was found that in SEBC, the levels of pro-inflammatory cytokines IL-6, IL-8, TNFα were increased by 1.4 times, compared to the parameters in BC, and the level of IL-8 was the highest. The total level of NF-kB increased by 14,7 times in patients with SEBC and by 2,4 times in patients with BC, compared to individuals with fibroadenomas. The level of NF-kB in SEBC in groups with IL-6, TNFα was higher than in groups with BC by 3.1 and 1,7 times, respectively. It was found that the highest level of NF-kB was in the group with cytokine IL-8. In SEBC, it was higher by 5.7 times than in BC. In patients with SEBC, correlations between NF-kB and cytokines were established: NF-kB and IL-8 (r = 0.80; p &lt; 0.05); NF-kB and IL-6 (r = 0.60; p &lt; 0.05); NF-kB and TNFα (r = 0.60; p &lt; 0.05). Thus, one feature of SEBC is the increase in the content of NF-kB, IL-6, and TNFα, and also a significant increase in the level of NF-kB and IL-8, compared to the parameters in patients with BC as well as in patients with fibroadenomas. Conclusions. It was found that there was activation of the transcription factor NF-kB-p105 and a significant increase in the levels of pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with SEBC, compared to patients with fibroadenomas, which indicates high carcinogenic potential of the tumor and the presence of the inflammatory component. It was demonstrated that the highest level of NF-kB-p105 was detected in the group of patients with SEBC with the highest level of cytokines IL-8. It was also found that in patients with SEBC, the level of the transcription factor and pro-inflammatory cytokines IL-6, IL-8, TNFα in the blood serum was significantly higher than in patients with BC, thereby confirming severe aggressiveness of this form of the disease.

Parameters of blood cytokine profile in male and female rats subjected to prenatal stress on the model of swimming in cold water (10°C, 5 min, days 10-16 of gestation) were studied. Prenatal stress had no significant effects on the blood levels of IL-6 and IL-10 cytokines. The blood concentration of proinflammatory cytokine TNFα in 60-day-old rats was higher than in age-matched controls. Stress led to a lower level of anti-inflammatory IL-4 in the blood of 30-day-old males compared to controls. In female rats subjected to prenatal stress, the concentration of IL-4 decreased on day 21, but increased by day 60 of postnatal ontogeny. Specific effects of prenatal stress on the blood cytokine profile in male and female animals at different periods of ontogeny were revealed. Different and even opposite changes in blood cytokine levels could be largely mediated by sex- and age-specific features of immune functions after prenatal stress.

Diabetes mellitus is associated with dyslipidemia, which contributes to a higher risk of thrombosis, atherosclerosis and cardiovascular disease. This study evaluated the effects of leucine and resistance training on the serum lipid profile in rats with streptozotocin-induced diabetes for 8 weeks. Wistar rats with neonatal streptozotocin-induced diabetes were treated with leucine supplementation (5%) and/or resistance training (3 days per week) for 8 weeks, and divided in DL (diabetic and leucine), DT (diabetic and resistance training group) and DLT (diabetic, leucine and resistance training) groups. Others 2 groups of animals received isonitrogen AIN-93M diet that was defined as a control diet: group D (diabetic untreated) and group C (non-diabetic). The decrease in serum total cholesterol and increase in high-density lipoprotein cholesterol (HDL-C) was observed in the resistance training-induced diabetic rats when compared with diabetic rats. There was no change in serum lipid profile in leucine-supplemented diabetic rats and no synergistic effect of leucine and resistance training. The fasting glucose levels were reduced in all animals treated compared to D group. The diabetic trained rats demonstrate a protective effect of resistance training on the serum lipid profile.

Nanotechnology includes nanosuspensions. Nanotechnology has become a huge area in the world of medicine. An appealing and promising approach to address the lipophilic like bio-available and poor solvability concerning the pharmaceuticals is nanosuspension. The majority of recently developed medications have poor water solubility. Drug formulation is usually complicated by medicines' limited water solubility. There are numerous standard methods for improving the solubility of pharmaceuticals that are poorly soluble, including Media Milling, Homogenization, precipitation technique, et cetera. A new approach in medication development is the development disintegrable medicinal formulations using nanotechnology. Particle sizes used in nanotechnology range are from 1 to 1000 nm. The increase in dissolving rate that results from drug particle size reduction into the submicron region naturally improves bioavailability. An efficient new method for improving the dissolution of low soluble in water medicines is nanosuspension technology. A nanosuspension improves the safety and effectiveness of a medicine by addressing issues with lipophilic like bio-available and poor solvability, as well as by changing the pharmacokinetics.

Systemic and exhaled cytokine and chemokine profiles are associated with the development of bronchiolitis obliterans syndrome

We sought to clarify the associations among serum cytokines, amino acid substitutions in the interferon sensitivity-determining region (ISDR) and core region, and treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.

Serum cytokines in ANCA-associated vasculitis: Correlation with disease-related clinical and laboratory findings