Chitosan Soft Matter Vesicles Loaded with Acetaminophen as Promising Systems for Modified Drug Release.

Our study was designed to acquire, characterize and evaluate the biocompatibility of novel lipid vesicles loaded with acetaminophen (APAP) and coated with chitosan (CS). We investigated the in vitro and in vivo drug release kinetics from these systems, and we conducted assessments for both in vitro hemocompatibility and in vivo biocompatibility. For the in vivo biocompatibility evaluation, the mice were randomly divided into four groups of six animals and were treated orally as follows: control group: 0.1 mL/10 g body weight of double-distilled water; CS group: 0.1 mL/10 g body weight 1% CS solution; APAP group: 150 mg/kg body weight APAP; APAP-v group: 150 mg/kg body weight APAP-loaded lipid vesicles. The impact of APAP-v on various hematological, biochemical, and immune parameters in mice were assessed, and the harvested tissues were subjected to histopathological examination. The innovative formulations effectively encapsulating APAP within soft vesicles exhibited reasonable stability in solution and prolonged drug release in both in vitro and in vivo studies. The in vitro hemolysis test involving APAP-loaded vesicles revealed no signs of damage to red blood cells. The mice treated with APAP-v showed neither significant variances in hematological, biochemical, and immune parameters, nor structural changes in the examined organ samples, compared to the control group. APAP-v administration led to prolonged drug release. We can conclude that the APAP-v are innovative carrier systems for modifying drug release, making them promising candidates for biomedical applications.

The Use of Chitosan-Coated Nanovesicles in Repairing Alcohol-Induced Damage of Liver Cells in Mice.

Background and Objectives In the past few decades, the studies concerning the natural polysaccharide chitosan have been centered on a new direction: its hepatoprotective action. The aim of our study was to evaluate the influence of previously designed chitosan lipid vesicles on the liver damage induced by alcohol consumption in mice. Materials and Methods The study involved the oral administration of substances in one daily dose as follows: Group 1 (control): water; Group 2 (control alcohol): 5% alcohol in water; Group 3 (CHIT): 0.1 mL/10 g body weight chitosan solution in animals treated with alcohol; Group 4 (CHIT-ves): 0.1 mL/10 g body chitosan vesicles in animals treated with alcohol; Group 5 (AcA): 200 mg/kg body ascorbic acid in animals treated with alcohol. In order to evaluate liver damage after alcohol consumption, the following hematological parameters were tested: the activity of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase; serum values of urea and creatinine; the phagocytic capacity of polymorphonuclear neutrophilsin peripheral blood;serum opsonic capacity;bactericidal capacity of peritoneal macrophages; and the activity of malondialdehyde, glutathione peroxidase, superoxide dismutase and lactate dehydrogenase. Results and Conclusions The treatment with chitosan vesicles decreased liver enzyme activity and reduced the oxidative stress disturbances in alcoholic mice, thus repairing the hepatic functional and structural damages. These beneficial activities of chitosan vesicles were comparable with ascorbic acid effects in alcoholic mice.

Magnesium Potentiates the Vortioxetine's Effects on Physical Performances and Biological Changes in Exercise-Induced Stress in Rats.

Background and objectives: Vortioxetine (VRT) is a relatively new selective serotonin reuptake inhibitor (SSRI) antidepressant and serotonin receptor modulator, approved for the treatment of major depression and generalized anxiety disorder. Depression has been linked with psychomotor disengagement, oxidative stress burden and decreased blood levels of brain-derived neurotrophic factor (BDNF). In our study we performed the experimental investigation of VRT, magnesium and of their association on the rats' endurance capacity, motor behavior and blood biological disturbances in rats subjected to forced exercise in treadmill test. Materials and Methods: The substances were administered orally for 14 consecutive days, as follows: group 1 (control): distilled water 0.3 mL/100 g body; group 2 (Mg): magnesium chloride 200 mg/kg body; group 3 (VRT): VRT 20 mg/kg body; group 4 (VRT+Mg): VRT 20 mg/kg body + magnesium chloride 200 mg/kg body. Magnesium was used as positive control substance with known effects in treadmill test. The consequences of VRT treatment on glucose, cortisol, BDNF and oxidative stress biomarkers (superoxide-dismutase, malondialdehyde, glutathione-peroxidase, lactate dehydrogenase) were also assessed. Results and conclusions: The use of VRT resulted in an improvement in motor capacity and an increase of the rats' endurance to physical effort. The administration of VRT increased the serum BDNF levels and reduced the oxidative stress in rats subjected to physical effort. The association of magnesium potentiated the effects of VRT on physical performances, the antioxidant activity and the decreasing in serum stress markers in treadmill test in rats.

Assessment of the In Vivo Release and Biocompatibility of Novel Vesicles Containing Zinc in Rats.

This paper is focused on the in vivo release and biocompatibility evaluation in rats of some novel systems entrapping zinc chloride in lipid vesicles. The particles were prepared by zinc chloride immobilization inside lipid vesicles made using phosphatidylcholine, stabilized with 0.5% chitosan solution, and dialyzed for 10 h to achieve a neutral pH. The submicrometric systems were physico-chemically characterized. White Wistar rats, assigned into four groups of six animals each, were treated orally with a single dose, as follows: Group I (control): deionized water 0.3 mL/100 g body weight; Group II (Zn): 2 mg/kg body weight (kbw) zinc chloride; Group III (LV-Zn): 2 mg/kbw zinc chloride in vesicles; Group IV (LVC-Zn): 2 mg/kbw zinc chloride in vesicles stabilized with chitosan. Haematological, biochemical, and immune parameters were assessed after 24 h and 7 days, and then liver fragments were collected for histopathological examination. The use of zinc submicrometric particles-especially those stabilized with chitosan-showed a delayed zinc release in rats. No substantial changes to blood parameters, plasma biochemical tests, serum complement activity, or peripheral neutrophils phagocytic capacity were noted; moreover, the tested substances did not induce liver architectural disturbances. The obtained systems provided a delayed release of zinc, and showed good biocompatibility in rats.

Evaluation of Antinociceptive Effects of Chitosan-Coated Liposomes Entrapping the Selective Kappa Opioid Receptor Agonist U50,488 in Mice.

Background and Objectives: The selective kappa opioid receptor agonist U50,488 was reported to have analgesic, cough suppressant, diuretic and other beneficial properties. The aim of our study was to analyze the effects of some original chitosan-coated liposomes entrapping U50,488 in somatic and visceral nociceptive sensitivity in mice. Materials and Methods: The influence on the somatic pain was assessed using a tail flick test by counting the tail reactivity to thermal noxious stimulation. The nociceptive visceral estimation was performed using the writhing test in order to evaluate the behavioral manifestations occurring as a reaction to the chemical noxious peritoneal irritation with 0.6% acetic acid (10 mL/kbw). The animals were treated orally, at the same time, with a single dose of: distilled water 0.1 mL/10 gbw; 50 mg/kbw U50,488; 50 mg/kbw U50,488 entrapped in chitosan-coated liposomes, according to the group they were randomly assigned. Results: The use of chitosan-coated liposomesas carriers for U50,488 induced antinociceptive effects that began to manifest after 2 h, andwere prolonged but with a lower intensity than those caused by the free selective kappa opioid in both tests. Conclusion: In this experimental model, the oral administration of nanovesicles containing the selective kappa opioid agonist U50,488 determined a prolonged analgesic outcome in the tail flick test, as well as in the writhing test.

Anxiolytic-like Activity, Antioxidant Properties, and Facilitatory Effects on the Short-Term Memory Retention of Molsidomine in Rats.

Compelling evidence indicates that nitric oxide (NO) exerts a significant influence on the central nervous system, participates in the modulation of neurotransmitter release, contributes to the regulation of cognitive functions, and plays a crucial role in modulating various aspects of neural activity. We aimed to explore the influence of two NO donors, molsidomine (MSD) and V-pyrro/NO, on the innate spontaneous psychomotor abilities and short-term memory in rats. Using an actimeter test, the locomotor activity, stress-sensitive behavior, and anxiety level were investigated. The influence on the animal`s cognitive functions was evaluated usingthe Y-maze test to assess the spontaneous alternation percentage, number of arms visited, number of alternations, and the preference index. Four distinct groups of five white male Wistar rats were exposed to the intraperitoneal treatments as follows: Control batch-0.3 mL/100 g of body weight saline solution, Mg batch-200 mg/kbwof magnesium chloride, MSD batch-1 mg/kbw of molsidomine, and V-pyrro/NO batch-5 mg/kbwof V-pyrro/NO. The intraperitoneal administration of MSD resulted in a significant reduction in spontaneous behavior and exploratory skills but was less pronounced than the positive control drug, magnesium chloride. Conversely, treatment with V-pyrro/NO led to only a slight decrease in horizontal movements during the actimeter test. MSD administration, but not V-pyrro/NO, notably increased the rate of spontaneous alternation in the Y-maze test. Additionally, the use of MSD resulted in an increase in the blood level of brain-derived neurotrophic factor and the intensification of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase activity. In our experimental setup, we demonstrated that MSD exposure led to a decrease in spontaneous behavior, showed anxiolytic effects and antioxidant activity, and improved spatial memory acquisition in rats.

Biocompatibility and Pharmacological Effects of Innovative Systems for Prolonged Drug Release Containing Dexketoprofen in Rats.

The present study reports on the in vivo biocompatibility investigation and evaluation of the effects of liposomes containing dexketoprofen in somatic sensitivity in rats. METHOD: The liposomes were prepared by entrapping dexketoprofen in vesicular systems stabilized with chitosan. The in vivo biocompatibility was evaluated after oral administration in white Wistar rats: Group I (DW): distilled water 0.3 mL/100 g body weight; Group II (DEX): dexketoprofen 10 mg/kg body weight (kbw); Group III (nano-DEX): liposomes containing dexketoprofen 10 mg/kbw. Blood samples were collected from caudal lateral vein one day and seven days after the substance administration, to assess the eventual hematological, biochemical, and immunological changes. The investigation of somatic pain reactivity was performed using the hot plate test, to count the latency time response evoked by the thermal paws' noxious stimulation. RESULTS: Original liposomes entrapping dexketoprofen, with mean size of 680 nm and good stability, were designed. Laboratory analysis indicated no substantial variances between the three treated groups. The treatment with liposomes containing dexketoprofen resulted in a prolongation of the latency time response, statistically significant in the interval between 90 min and 10 h, in the hot plate test. CONCLUSIONS: The use of liposomes with dexketoprofen proved a good in vivo biocompatibility in rats and prolonged analgesic effects in the hot plate test.

The Analysis of Chitosan-Coated Nanovesicles Containing Erythromycin-Characterization and Biocompatibility in Mice.

Nanoantibiotics have proved improved pharmacokinetic characteristics and antimicrobial features. Recent studies have shown non-toxicity, non-immunogenicity, antioxidant, anti-hyperlipidemic, and hepatocyte protective actions, among other advantages of chitosan-based nanoparticles. The purpose of our study was the structural analysis of novel chitosan-coated vesicles entrapping erythromycin (ERT) and the assessment of their biocompatibility in mice. According to the group in which they were randomly assigned, the mice were treated orally with one of the following: distilled water; chitosan; ERT; chitosan vesicles containing ERT. Original nanosystems entrapping ERT in liposomes stabilized with chitosan were designed. Their oral administration did not produce sizeable modifications in the percentages of the leukocyte formula elements, of some blood constants useful for evaluating the hepatic and renal function, respectively, and of some markers of oxidative stress and immune system activity, which suggests a good biocompatibility in mice. The histological examination did not reveal significant alterations of liver and kidney architecture in mice treated with chitosan liposomes entrapping ERT. The results indicate the designed liposomes are a promising approach to overcome disadvantages of conventional ERT treatments and to amplify their benefits and can be further studied as carrier systems.

Immunological approaches and therapy in burns (Review).

Burns have become an important public health problem in the last two decades, with just over a quarter of a million deaths annually. Major burns are accompanied by a strong inflammatory response, which will most often lead to systemic response inflammatory syndrome, followed by sepsis and finally induce multiple organ failure. The main mechanism involved in wound healing after burns is the inflammatory process, characterized by the recruitment of myeloid and T cells and by the involvement of numerous cytokines, chemokines, complement fractions, as well as various growth factors. Inflammasomes, protein-based cytosolic complexes, activated during metabolic stress or infection, play a role in modulating and improving the defense capacity of the innate immune system. Nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome has been studied predominantly and several hypotheses have been issued. Restoring the balance between the pro-inflammatory response and the anti-inflammatory activity is the key element to effective therapy in burns. Severe burns require nutritional support and pharmacotherapy not only for burn area but for different pathological complications of burn injury. In-depth research is required to find new ways to modulate the defense capacity, to prevent the complications of abnormal immune response and to treat burn injuries efficiently.

New Nitric Oxide Donors With Therapeutic Potential.

Nitric oxide (NO), formerly known as the endothelium-derived relaxing factor, is a mediator with a key role in the body, both in the central nervous system and in periphery. NO is synthesized by several cell types, where it acts as an autocrine and paracrine signaling molecule. Harnessing the impressive therapeutic potential of nitric oxide (NO) remains an ongoing challenge. In order to overcome the limitations linked with the use of nitric oxide and specially to increase the release of the radical in the targeted area, promising therapeutic strategies have been implemented, based on specific technologies which create releasing agents and vehicles for nitric oxide. Organic nitrites are the most known NO donor drugs, used especially in the treatment of cardiovascular diseases. In recent years, technological advances have allowed obtaining variations synthetic derivatives (such as diazeniumdiolates, S-nitrosothiols), which can generate NO in a controlled mode in the body and to chemically stabilize it; these compounds were studied with promising results in various animal models of vasospasm and pulmonary hypertension. Another high value therapeutic path is represented by the development of hybrid drugs (new nonsteroidal anti-inflammatory NO donor agents), with practical applications in inflammatory disorders accompanied by pain. Also, there is increasing evidence of the existence of NO donors with important antioxidant and hepatoprotective effects.