Formulation of hesperidin-loaded in situ gel for ocular drug delivery: a comprehensive study.

BACKGROUND: Allergic conjunctivitis is one of the most common eye disorders. Different drugs are used for its treatment. Hesperidin is an active substance isolated from Citrus sinensis L. (Rutaceae) fruit peels, with known anti-inflammatory activity but low solubility. It was complexed with cyclodextrin and encapsulated in situ gel to extend its duration in the eye. RESULTS: The optimized formulation comprised 1% hesperidin, 1.5% hydroxyethyl cellulose, and 16% poloxamer 407. The viscosity at 25 °C was 492 ± 82 cP, and at 35 °C it was 8875 ± 248 cP, the pH was 7.01 ± 0.03, gelation temperature was 34 ± 1.3 °C, and gelation time was 33 ± 1.2 s. There was a 66% in vitro release in the initial 2 h, with a burst effect. A lipoxygenase (LOX) inhibition test determined that hesperidin was active at high doses on leukotyrens seen in the body in allergic diseases. In cell-culture studies, the hesperidin cyclodextrin complex loaded in situ gel, BRN9-CD (poloxamer 16%, hydroxy ethyl cellulose (HEC) 1.5%), enhanced cell viability in comparison with the hesperidin solution. It was determined that BRN9-CD did not cause any irritation in the ocular tissues in the Draize test. CONCLUSION: The findings of this study demonstrate the potential of the in situ gel formulation of hesperidin in terms of ease of application and residence time on the ocular surface. Due to its notable LOX inhibition activity and positive outcomes in the in vivo Draize test, it appears promising for incorporation into pharmaceutical formulations. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Mutagenic effects of nitrogen protoxide and oryzalin on "41 B" and "Fercal" grapevine rootstocks seedlings.

In this study, the mutagenic effects of different doses and exposure times of oryzalin and Nitrogen Protoxide (N2O) were tested for stimulating polyploid on 41 B and Fercal grapevine rootstocks seedlings. Ploidy changes were examined by morphological, cytological, macroscopic, and microscopic methods. Leaf thickness, chlorophyll contents, stomatal sizes, and chloroplast numbers of polyploid seedlings stimulated with mutagens increased but their stomatal densities decreased. Flow cytometry (FC) analyses were performed on 50 samples selected by morphological and microscopic preliminary determinations. In FC analyses, 1 tetraploid seedling and 4 mixoploid seedlings from Fercal offspring and 1 mixoploid seedling from 41 B offspring were verified. The nuclear DNA content of tetraploid and mixoploid seedlings were increased by 2.00 and 1.34-fold, respectively, when compared to their diploid parents. Chromosome counts in root tip samples propagated in vitro from the tetraploid Fercal offspring confirmed a 2-fold increase compared to the diploid parent. In polyploidy induction studies, it was deemed appropriate to use FC analysis and chromosome count together to confirm the ploidy levels of mutants. Oryzalin and N2O applications at different doses and exposure times were found to be effective for inducing polyploidy in 41 B and Fercal grapevine rootstocks.

Formulation development of Lornoxicam loaded heat triggered ocular in-situ gel using factorial design.

OBJECTIVE: In the current research, lornoxicam-loaded in situ gels were developed, and their potential usage in ocular inflammation was evaluated. SIGNIFICANCE: Lornoxicam cyclodextrin complex prepared with hydroxypropyl methylcellulose and poloxamer P407 because of the low viscosity of in situ gels to provide easy application. However, washing and removing it from the ocular surface becomes difficult due to the gelation formation with heat. METHODS: A three-level factorial experimental design was used to evaluate the effects of poloxamer 407 concentration, polymer type, and polymer concentration on viscosity, pH, gelation capacity, gelation time, and gelation temperature, which were considered the optimal indicators of lornoxicam-containing formulations. RESULTS: As a result of the three-level factorial experimental design, the optimized formulation contained 15 (%w/v) poloxamer 407 and 1 (%w/v) hydroxypropyl methylcellulose. The optimize formulation viscosity 25 °C = 504 ± 49cP, viscosity 35 °C = 11247 ± 214cP, pH = 6.80 ± 0.01, gelation temprature = 35 ± 0.2 °C, and gelation time= 34 ± 0.2 s was obtained. In the in vitro release studies, 68% of lornoxicam was released with a burst effect in the first three hours; then, the release continued for eight hours with controlled release. Release kinetics of the formulations were modeled mathematically, and it was found to be compatible with the Korsemeyer-Peppas and Weibull models. In cell culture studies, cell viability at 100 µg/mL was 83% and 96% for NL6 and NL6-CD, respectively. In Draize's in vivo test, no negative conditions occurred in rats. CONCLUSIONS: Therefore, the NL6-CD formulation has the potential to be a favorable option for treating ocular inflammation.

Prognostic Significance of Pan-Immune-Inflammation Value in Patients with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab Emtansine.

Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan-Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569-0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408-3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585-3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.

Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics.

Intestinal cancers are the third most lethal cancers globally, beginning as polyps in the intestine and spreading with a severe metastatic tendency. Chemotherapeutic drugs used in the treatment of intestinal tumors are usually formulated for parenteral administration due to poor solubility and bioavailability problems. Pharmaceutically, clinical failure due to a drug's wide biodistribution and non-selective toxicity is one of the major challenges of chemotherapy. In addition, parenteral drug administration in chronic diseases that require long-term drug use, such as intestinal tumors, is challenging in terms of patient compliance and poses a burden in terms of health economy. Especially in the field of chemotherapy research, oral chemotherapy is a subject that has been intensively researched in recent years, and developments in this field will provide serious breakthroughs both scientifically and socially. Development of orally applicable nanodrug formulations that can act against diseases seen in the distant region of the gastrointestinal tract (GIT), such as intestinal tumor, brings with it a series of difficulties depending on the drug and/or GIT physiology. The aim of this study is to develop an oral nanoparticle drug delivery system loaded with docetaxel (DCX) as an anticancer drug, using poly(lactic-co-glycolic acid) (PLGA) as nanoparticle material, and modified with chitosan (CS) to gain mucoadhesive properties. In this context, an innovative nanoparticle formulation that can protect orally administered DCX from GIT conditions and deliver the drug to the intestinal tumoral region by accumulating in mucus has been designed. For this purpose, DCX-PLGA nanoparticles (NPs) and CS/DCX-PLGA NPs were prepared, and their in vitro characteristics were elucidated. Nanoparticles around 250-300 nm were obtained. DCX-PLGA NPs had positive surface charge with CS coating. The formulations have the potential to deliver the encapsulated drug to the bowel according to the in vitro release studies in three different simulated GIT fluids for approximately 72 h. Mucin interaction and penetration into the artificial mucus layer were also investigated in detail, and the mucoadhesive and mucus-penetration characteristics of the formulations were examined. Furthermore, in vitro release kinetic studies of the NPs were elucidated. DCX-PLGA NPs were found to be compatible with the Weibull model, and CS/DCX-PLGA NPs were found to be compatible with the Peppas-Sahlin model. Within the scope of in vitro cytotoxicity studies, the drug-loaded NPs showed significantly higher cytotoxicity than a DCX solution on the HT-29 colon cell line, and CS/DCX-PLGA showed the highest cytotoxicity (p < 0.05). According to the permeability studies on the Caco-2 cell line, the CS/DCX-PLGA formulation increased permeability by 383% compared to free DCX (p < 0.05). In the light of all results, CS/DCX-PLGA NPs can offer a promising and innovative approach as an oral anticancer drug-loaded nanoformulation for intestinal tumors.

The role of hypoxia at primary dysmenorrhea, utilizing a novel hypoxia marker--SCUBE1.

STUDY OBJECTIVE: To determine the SCUBE1 levels in adolescents with primary dysmenorrhea. DESIGN: A prospective cross-sectional study. SETTING: A university hospital outpatient clinic, Rize, Turkey. PARTICIPANTS: A total of 40 adolescent girls, 15 on menses and 25 not on menses. INTERVENTIONS AND MAIN OUTCOME MEASURES: Demographic features and menstrual history of the participants were assessed and blood samples were obtained for detecting the platelet volume, platelet counts, and SCUBE1 levels of the participants. RESULTS: No difference was detected between the 2 groups in mean platelet volume, platelet count, and SCUBE1 levels. CONCLUSION: Future trials are required to investigate the relation between SCUBE1 levels and primary dysmenorrhea.

The effects of simultaneous prompting on teaching receptively identifying occupations from picture cards.

A multiple probe across subjects design was used to examine whether or not the use of simultaneous prompting procedure would result in an increase on the percentage of correct responding of receptively identifying occupations from picture cards. Maintenance and generalization effects of simultaneous prompting were also investigated. Five occupations were taught to each subject. Black and white picture cards were used to explain occupations during full and daily probe, instructional and maintenance probe sessions. Colored picture cards were used during generalization sessions and generalization probe was assessed before and after instruction. Maintenance sessions were conducted 1, 2, and 4 weeks after the instruction. Maintenance and generalization probe sessions were conducted just like full probe sessions. Fifteen trials were used during full and maintenance probe sessions and 10 trials during daily probe, instructional, and generalization probe sessions. Correct responses resulted in reinforcement in all sessions whereas incorrect responses resulted with error correction during instructional sessions and ignorance during daily, full, maintenance, and generalization probe sessions. Simultaneous prompting was effective for teaching receptively identifying occupations form picture cards. Maintenance and generalization effects of simultaneous prompting were also positive. Future research is needed to extend the current literature about simultaneous prompting.

Alterations of natriuretic peptides amino-terminal pro B-type natriuretic peptide and amino-terminal pro C-type natriuretic peptide during the pregnancy.

OBJECTIVE: The aim of this study was to determine the plasma levels of natriuretic peptides amino-terminal pro B-type natriuretic peptide (NT proBNP) and amino-terminal pro C-type natriuretic peptide (NT proCNP) during pregnancy and any possible changes occurring in each trimester. METHODS: This was a prospective longitudinal case-control study conducted in a University Hospital antenatal outpatient clinic. Subjects were all healthy pregnant women without a history of previous cardiac disease, hypertension or preeclampsia, and each patient was assessed during every trimester, and blood samples were collected for the measurement of NT proBNP and NT proCNP levels. RESULTS: Twenty pregnant women were followed-up during pregnancy without any complications. We obtained longitudinal levels of natriuretic peptides in each trimester. The mean NT proBNP levels were 14.95 ± 16.8, 9.37 ± 10.76, 52.48 ± 126.65 pmol/ml and the mean NT proCNP levels were 44.64 ± 41.64, 45.70 ± 47.03, 47.22 ± 55.09 pmol/l, respectively. No statistically significant alteration of plasma levels of natriuretic peptides was detected between trimesters. CONCLUSION: This is the first study evaluating the longitudinal levels of NT proCNP during the pregnancy, and demonstrates that NT proCNP remained constant, but NT proBNP levels do not significantly alter during pregnancy.