Ocular pharmacokinetics and toxicity of nanoparticular acetazolamide: In vivo distribution and safety of PHBV-ACZ nanoparticle.

Diabetic macular edema (DME) is defined as fluid accumulation in the macular region, between the retinal layers, due to many diseases, especially diabetes. DME is one of the major complications of diabetic retinopathy (DRP). Carbonic anhydrase inhibitors (CAI) are a pharmaceutical agent used in different fields, especially glaucoma treatment. Acetazolamide (ACZ), which is a CAI, is an active substance that has been used off-label for many years in the treatment of macular edema due to diabetes and many other diseases. The low solubility and bioavailability of ACZ limit its use in the treatment of DME. In this study, a nanoparticulate formulation was developed that would increase the solubility and bioavailability of ACZ and allow it to be administered intravitreally. ACZ was loaded on poly(3-hydroxybutyrate-co-3-Hydroxyvalerate) (PHBV) nanoparticles and the loading efficiency was 71.58 ± 1.22%. Toxicity of nanoparticles after intravitreal application was evaluated with anterior segment and posterior segment examination findings, intraocular pressure (IOP) measurements and electrophysiological tests. At the end of the 3-month follow-up, electroretinography (ERG) measurements demonstrated that ACZ loaded PHBV (PHBV-ACZ) nanoparticles did not cause loss of function in retinal cells. On histological examination, rare degenerative changes were observed in several cell groups. In addition, pharmacokinetic studies were performed to determine the tissue distribution of ACZ at various periods. ACZ was identified in vitreous humor and retina at the highest concentration. Based on our results, the prepared nanoparticle formulation can release long-term CAI for DRP therapy and accordingly can reduce the need for monthly intravitreal injections.

The Bioequivalence Study of Two Dexketoprofen 25 mg Film-Coated Tablet Formulations in Healthy Males Under Fasting Conditions.

Objectives: Dexketoprofen is a non-steroidal analgesic/anti-inflammatory drug and its trometamol salt is extensively preferred in mild or moderate pain due to its rapid onset of relief. A new formulation of 36.9 mg of dexketoprofen trometamol (equivalent to 25 mg dexketoprofen) tablet has been developed and its bioequivalence to the reference product was proven. Materials and Methods: An open-label, single-dose, randomized, two-period, and cross-over bioequivalence study was conducted with healthy males under fasting conditions for two different tablet formulations of 25 mg dexketoprofen. To prove the bioequivalence of the test product with the reference product, a comparison study has been performed in compliance with regulations in force under Good Clinical Practice principles. A single-center clinical study was run and blood samples of the participants were withdrawn at specified time points, before and after dosing, to measure the plasma concentrations of dexketoprofen trometamol. A validated analytical method has been developed using an liquid chromatography with tandem mass spectrometry. Instrument to assess the plasma concentrations of the test and reference products. Results: Forty-seven volunteers completed clinical phase of the study. For the test and reference products, the mean ± standard deviations (SD) of Cmax were found 2543.82 ± 655.42 ng/mL and 2539.11 ± 662.57 ng/mL, and the mean ± SD of area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-tlast) were found 3483.49 ± 574.42 h.ng/mL and 3560.75 ± 661.83 h.ng/mL, respectively. The primary target variables data demonstrate the bioequivalence of test and reference products with regard to 90% confidence interval for Cmax of 92.45-108.53% and for AUC0-tlast of 95.57-100.87%. The geometric mean ratios were found as 100.16% and 98.18% for Cmax and AUC0-tlast, respectively. There were no serious adverse events or adverse reactions reported throughout the study. Conclusion: After statistical evaluation of the analytical results, the test and reference products were considered bioequivalent. Both products were well tolerated and considered as safe.

Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation.

Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex®, and faster tmax 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).

Potential ameliorative effect of dietary quercetin against lead-induced oxidative stress, biochemical changes, and apoptosis in laying Japanese quails.

Lead (Pb) is a widespread environmental pollutant which is a toxic threat to human and animal health. The present study was designed to evaluate the ameliorative role of quercetin in laying quails exposed to Pb. A total of 112 birds were randomly divided into four groups. The control group was fed with basal diet, the Pb group was fed with ration supplemented with Pb at the dose of 100 mg/kg (as Pb (II) acetate trihydrate), the Quercetin group was fed with ration supplemented with quercetin at the dose of 400 mg/kg, and the Pb+ Quercetin group was fed with ration supplemented with Pb at the dose of 100 mg/kg and quercetin at dose of 400 mg/kg. Results showed that serum total protein, glucose, albumin, and blood urea nitrogen (BUN) values of the Pb + Quercetin group partially improved with quercetin supplementation. Meanwhile, serum creatinine values of the Pb + Quercetin group was found to be significantly lower than that of the Pb group. Aspartate aminotransferase (AST) and alanine transaminase (ALT) enzyme activities in the Quercetin and Pb + Quercetin groups were similar to those of the Control group, unlike the Pb group. Moreover, alkaline phosphatase (ALP) enzyme activity of the Pb + Quercetin group significantly improved with the addition of quercetin. We also found that malondialdehyde (MDA) levels of the kidney, liver, and heart were significantly reduced by quercetin supplementation. The glutathione, catalase, and glutathione peroxidase activities of the kidney, liver, and heart tissue were increased by quercetin supplementation. These results were in line with the observed apoptotic markers. The expression of caspase-3 and caspase-9 were significantly decreased by quercetin supplementation. It may be concluded that dietary supplementation with quercetin ameliorates the toxic effects of Pb exposure by alleviating oxidative stress, biochemical changes, and apoptosis in quails.

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

Ellagic acid plays an important role in enhancing productive performance and alleviating oxidative stress, apoptosis in laying quail exposed to lead toxicity.

Lead (Pb) is one of the most toxic heavy metal environmental pollutants due to its widespread use of the industry and it is a harmful substance for human and animal health. This study was conducted to investigate the potential protective effects of ellagic acid (EA) on performance, egg quality, antioxidant parameters, and apoptotic pathway proteins in laying quails exposed to Pb toxicity. A total of 168 (15-week old) laying quails (Coturnix coturnix Japonica) were divided into 6 experimental groups (with similar initial average body weight). Birds were fed 1 of 6 diets for 8 weeks: 1 - Control (basal diet), 2 - Pb (basal diet + 100 mg/kg Pb), 3 - EA-300 (basal diet + 300 mg/kg EA), 4 - EA-500 (basal diet + 500 mg/kg EA), 5 - Pb + EA-300 (basal diet + 100 mg/kg Pb + 300 mg/kg EA), 6 - Pb + EA-500 (basal diet + 100 mg/kg Pb + 500 mg/kg EA). The results showed that adding 100 mg/kg of Pb to basal diet was adversely affected the performance parameters and, feed intake and egg production were significantly decreased by Pb supplementation (P < 0.01). However, the EA supplementation to Pb groups improved the performance parameters. Compared with the Pb alone group, in Pb + EA-500 group increased egg production by 8.4%. There were no significant differences in the Haugh unit, albumen index, and yolk index among groups (P > 0.05). Liver and kidney tissues of Pb group malondialdehyde (MDA) level increased (P < 0.001) and, GSH, GSH-Px, and CAT values decreased (P < 0.001) but, EA supplementation alleviated this condition (P < 0.001). The protein levels of caspase-3 and -9 were significantly increased in the Pb group compared to the control group, whereas EA supplementation alleviated the Pb-induced apoptosis by decreasing caspase-3 and -9 levels in the liver tissue (p < 0.001). In laying quails exposed to Pb toxicity, EA supplementation improves the performance parameters, enhances the antioxidant defense system, and suppresses apoptosis via regulates the expression of caspase-3 and -9. Thus, it was concluded that EA (especially 500 mg/kg) can ameliorate the toxic effects of Pb exposure in quails.

The protective effect of chrysin against carbon tetrachloride-induced kidney and liver tissue damage in rats.

The aim of this study was to investigate the possible protective effects of chrysin on oxidative status and histological alterations against carbon tetrachloride (CCl4)-induced liver and kidney tissue in rats. The animals were randomly divided into four groups; the control, chrysin (100 mg/kg), CCl4 (0.5 ml/kg) and chrysin + CCl4 groups. Liver and kidney injuries were assessed by biochemical and histopathological examinations. The levels of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) activity were measured in tissues. Serum tumor necrosis factor-α (TNF-α), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine levels were also measured in blood samples. MDA, serum TNF-α, AST, ALT, urea, and creatinine levels (p < 0.05) were significantly higher, and SOD activity and GSH level were significantly (p < 0.05) lower in the CCl4 group than in the control group. Treatment with chrysin in the chrysin + CCl4 group decreased MDA, AST, ALT, creatinine, and TNF-α levels (p < 0.05), and increased SOD activity, GSH levels (p < 0.05), and serum TNF-α levels (p < 0.05). In addition, body weight change (BWC) (p < 0.05) and feed intake (FI) were significantly lower (p < 0.001) in the CCl4 group than in the control group. Moreover, treatment with chrysin increased BWC and FI in the chrysin + CCl4 group compared with that in the CCl4 group. These findings also confirmed by histopathological examination. The chrysin treatment ameliorated the CCl4-induced biochemical and pathological alterations. These results demonstrated that chrysin provided amelioration on the rat liver and kidney tissues CCl4-induced injury by increasing the antioxidant activity.

Health behaviors in high school students in Izmir, Turkey.

AIM: The aim of this cross-sectional study was to determine the prevalence of the self reported health behaviors and differences in these behaviors by gender and grades in high school adolescents in Izmir, Turkey. MATERIAL AND METHODS: A stratified cluster sampling procedure was used for this cross-sectional study. The study sample included 2 296 students attending 22 high schools in Izmir. As a data collection instrument, some questions from the Health Behavior in School-aged Children Study 2009/2010 questionnnaire and questions which were developed by the researchers to understand behaviors of internet use in adolescents were used. Chi-square tests and Cramer's V statistics were used for statistical analyses. RESULTS: Among the high school students, 33.8% experimented smoking, 26.3% smoked cigarette during the 30 days before the survey, 14.9% smoked cigarette regularly during the 30 days before the survey, 54.1% experimented drinking alcohol, 38.4% drunk alcohol during the 30 days before the survey, 31.6% got drunk, 10.9% were adequately physically active, 59.9% watched TV for a long period of time, 72.8% used internet for a long period of time, 48.1% ate breakfast regularly, 36.2% ate adequate amount of fruit, 14.1% ate adequate amount of vegetable, 31.3% ate candies and chocolate very often, 18% drunk soft drink very often, 30.3% were bullied, 29.9% bullied others and 41% involved in a physical fight. CONCLUSIONS: These results showed that "Adolescent friendly health services" should be generalized all over Turkey, physicians should evaluate each adolescent for his/her health behaviors in each visit and implementation of prevention programs which adopt a health promotion perspective is necessary begining from the elementary school.