Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study.

Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of - 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (131I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.

Outcomes Of Mesh Fixation Versus Non Fixation In Laparoscopic Transabdominal Preperitoneal Inguinal Hernia Repair: A Randomized Clinical Study.

Objectives: The present study aimed to compare the results of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair with and without mesh fixation regarding postoperative pain, recurrence, operative time, and complications. METHODS: This randomized controlled clinical trial included 100 patients who underwent TAPP inguinal hernia with mesh fixation (group A) or a fixation-free procedure (group B) for early onset inguinal hernia at the General Surgery Department, Kafrelsheikh University Hospital, from January 2021 to June 2022. RESULTS: The parameters for pain assessment (NRS) in the first week (mean 7 (5 - 8)), the first month (mean 3 (1 - 5)), and after three months(mean 0 - (70% of patients), (mean 1- (30% of patients) were significantly higher in the fixation group (p<0.001). The fixation group had significantly more operative time than non fixation, with a mean (69.34±13.55, 60.92±10.18) respectively. Recurrence rate and postoperative complications did not show any significant difference between the studied groups. CONCLUSIONS: Mesh non-fixation for laparoscopic TAPP hernia repair is safe, practical, and effective with minimal postoperative pain and no increased risk of recurrence.

Effect Of Laparoscopic Sleeve Gastrectomy On Vitamin D, Parathormone Hormone, And Serum Calcium Levels.

Objectives: To evaluate the effect of laparoscopic sleeve gastrectomy on vitamin D status, parathyroid hormone,serum calcium and the effectiveness of vitamin D supplementation. Method: The prospective study was conducted at the General Surgery Department of Kafrelsheikh University Hospital, Egypt, in November 2019, and comprised morbidly obese patients of either gender who were managed with laparoscopic sleeve gastrectomy. Serum levels of vitamin D, calcium and parathyroid hormone were assessed at baseline and at 6 and 12 months after the surgery. All subjects were given 400 IU/day of vitamin D. If the level of vitamin D was <30ng/ml, further doses of calcifediol 200,000 IU were added every two weeks. Data was analysed using SPSS 22. RESULTS: Of the 40 patients, 28(70%) were females and 12(30%) were males. The overall mean age was 33.9±10.8, mean weight was 136±18.29kg and mean body massindex was 50±4.9kg/m2 . The mean operative time was 64.5±13.6 minutes, and the mean hospitalstay was 1.8±1.1 days. There wassignificant reduction in body massindex values after the surgery (p<0.05). Vitamin D level was 19.2±3.2 ng/ml at baseline, which rose to 21.4±2.7 ng/ml at 6 months and 26.6±2.8 ng/ml at 12 months post-surgery (p<0.05). Preoperative parathyroid hormone level was 58.3±7.8 pg/ml , which went down to 48.6±7.4 pg/ml at 6 months, and 41.3±6.5 pg/ml at 12 months postoperatively (p<0.05). The mean serum calcium level at baseline was 9±0.4mg/dL, which rose to 9.2 ±0.3mg/dL and 9.5±0.4 mg/dL at 6 and 12 months post-surgery (p<0.05). CONCLUSIONS: Low vitamin D complications could be decreased postoperatively by administering vitamin D as a routine treatment. Postoperative monitoring of vitamin D, parathyroid hormone and serum calcium levels is essential.

Dietary inclusion of nano-phosphorus improves growth performance, carcass quality, and growth-related traits of Nile tilapia (Oreochromis niloticus) and alleviates water phosphorus residues.

Supplementation of phosphorus nanoparticles is a promising strategy to reduce water pollution, improve phosphorus concentration in fish diet, and provide better production quality. We used 300 fingerlings of Nile tilapia that were randomly distributed into 3 groups; each one was attributed to 5 replicates of 20 fish per aquarium with initial weight (gm) (156 ± 1.25). The first diet contained traditional Di-calcium phosphate (D-group), the second supplemented with phosphorus nanoparticles in a dose equal to the previous conventional one (N-D group), and the last one included with phosphorus nanoparticles with the half dose of the conventional phosphorus group (1/2 N-D group). After 3 months of feeding, the N-D group showed the best growth performance including its feed conversion ratio (FCR), feed intake (FI), or body weight gain (BWG). Furthermore, the growth-related gene expression findings considering growth hormone receptor (GHR) and insulin-like growth factor-1 (IGF-1) were upregulated as well. Moreover, whole body chemical composition revealed higher Fe, Zn, P, and crude protein level in the N-D group than the other two groups. Lipoprotein lipase (LPL) and fatty acid synthetase (FAS) mRNA expression showed a significant increase in 1/2 N-D and N-D groups compared with the control group. To sum up, using of nano-phosphorus particles improved the growth rate and immunity response of Nile tilapia, besides decreasing water pollution.

The optimized inclusion level of Bacillus subtilis fermented Azolla pinnata in Nile tilapia (Oreochromis niloticus) diets: immunity, antioxidative status, intestinal digestive enzymes and histomorphometry, and disease resistance.

A 95-day feeding trial was conducted to evaluate the outcomes of feeding Bacillus subtilis fermented Azolla (BSFA) on nonspecific immunity, antioxidative status, intestinal digestive enzymes and histomorphometry, and disease resistance in the Nile tilapia. We formulated five isonitrogenous and isocaloric experimental diets to incorporate BSFA at level of (0%, 15%, 30%, 45%, 60%). The growth performance parameters (FBW, BWG, SGR, PER, and FCR) revealed a significant increase in the BSFA30 tilapia group compared to the control group followed by BSFA45 (P < 0.05). The BSFA30 group exhibited the highest nonspecific immunity parameters including (lysozyme activity, phagocytic index, and phagocytic activity) compared to other groups (P < 0.05). SOD and GPx reported the highest values in the BSFA60 group. Nile tilapia carcass composition was not influenced by BSFA inclusion level (P > 0.05). Interestingly, Nile tilapia fed with BSFA15 diet exhibited the highest protease activity level (P < 0.05), while those fed on BSFA30 documented the highest amylase activity. Intestinal histomorphology was significantly enhanced with the gradual increase of administrated BSFA. Regarding the tilapia disease resistance against Aeromonas septicemia, BSFA significantly diminished the cumulative mortality compared to the control group. To sum up, BSFA was more effective in improving the growth performance and immunity of Nile tilapia.

Early Postoperative Sequelae After Open Sky Access in Nasal Osteotomy: A Comparative Study.

INTRODUCTION: Nasal osteotomy is a powerful cornerstone step in almost all rhinoplasty procedures and is a major cause of postoperative periorbital ecchymosis and edema after rhinoplasty. Different accesses for osteotomy have been described, the most popular of which is the external perforating and the internal continuous methods. These accesses are blind maneuvers and have some drawbacks such as possible visible scar formation in the percutaneous access or high rate of mucosal tear in the endonasal access. Open sky access osteotomy after wide subperiosteal dissection had been described to overcome those disadvantages. Early postoperative sequelae have not been assessed in the literature after using this access. In the present study, we aim to assess early postoperative sequelae after using this technique in comparison with percutaneous perforating osteotomy. MATERIALS AND METHODS: The study was conducted between November 2017 and January 2021. Forty patients were randomly assigned into 2 equal groups. Group A was subjected to lateral osteotomy by percutaneous perforating method, whereas group B underwent lateral osteotomy by the open sky access technique using a 2-mm curved osteotome. Early postoperative periorbital sequelae were assessed on the second and seventh postoperative days, using the grading system suggested by Kara et al (Plast Reconstr Surg. 1999;104:2213-2218). Mucosal tear was assessed on the second postoperative day using nasal endoscopy after removal of nasal packs. RESULTS: There was a statistically nonsignificant difference between the studied groups regarding ecchymosis and edema occurring on the second or seventh days. Meanwhile, mucosal tear was significantly less in the open sky access osteotomy group. CONCLUSIONS: Open sky access osteotomy is a safe method for lateral nasal osteotomy with direct visualization of the surgical field. It does not require a skin incision that could lead to a scar formation. It produces less mucosal tear than percutaneous perforating osteotomy. No statistically significant difference is found between both techniques regarding postoperative periorbital ecchymosis and edema on the second and seventh postoperative days.

Preparation, characterization, and in vivo biodistribution study of intranasal 131I-clonazepam-loaded phospholipid magnesome as a promising brain delivery system.

OBJECTIVE: Clonazepam (CP) is a potent long-acting nitrobenzodiazepine derivative that could be used for targeting peripheral benzodiazepine receptors. Phospholipid magnesome is a new vesicular nanosystem recently developed for brain targeting. Improving the uptake of 131I-CP to the brain might be effective for the diagnosis and/or radiotherapy of certain brain diseases and/or tumors. METHODS: CP was radiolabeled with 131I using direct electrophilic substitution reaction. Quality control of 131I-CP was performed using different techniques. Different formulas of 131I-CP were prepared and characterized according to particle size and polydispersity index. The structural features of the optimized formula were then interpreted using transmission electron microscopy and scanning electron microscopy, whereas pharmacokinetic and in vivo behaviors were estimated using the intravenous and intranasal delivery routes. RESULTS: The heart and blood demonstrated lower uptake of 131I-CP, which inevitably decreased the nontarget effects of radioiodine. Intranasally administered 131I-CP-loaded magnesomes (INMg) had noticeably higher brain uptake (7.1 ± 0.09%ID/g) with rapid onset of action within 5 min and effective pharmacokinetic behavior. INMg had a drug targeting efficiency and nose-to-brain direct transport percentage of 121.1% and 94.6%, respectively as well as a relative bioavailability of 441.04 ± 75.5%. CONCLUSION: The present study showed that 131I-CP-loaded magnesomes can be a beneficial brain-targeting approach for improving the diagnosis and/or radiotherapy of certain brain diseases.

Gut immune-related gene expression, histomorphometry and hematoimmunological assays in Nile tilapia (Oreochromis niloticus) fed Aspergillus oryzae fermented olive cake.

Fermentation strategy is well documented to improve the nutritional value of agricultural waste by-products such olive cake (OC), which, in turn, provides healthy, safe, and affordable feedstuff. This study assessed the combined impact of Aspergillus oryzae-fermented OC (AFOC) on the growth performance, intestinal morphometry, blood biochemistry, lysozyme activity, gut immune-related genes, and flesh quality of Nile tilapia. We divided 225 fish into five groups and further subdivided into three replicates (n = 15 each) and fed them five diets (Control, AFOC5, AFOC10, AFOC15, AFOC20) to determine AFOC nutritional value and its optimized incorporation level in the diet. The trial continued for 3 months. The crude protein content of OC improved by 7.77% after A. oryzae fermentation, while lipid content decreased by 14.19%. In addition, growth and feed utilization significantly improved at (10.8-11.2) % AFOC dietary level. High-density lipoprotein (HDL) significantly improved, and the serum lysozyme level was significantly higher in the AFOC10 group compared to other groups. Interestingly, gut-related inflammatory cytokines tumor necrosis factor alpha (TNF- α) and interleukin 1 beta (IL-1ß) revealed higher relative mRNA expression in the AFOC10 group compared to other groups. The histomorphometric parameters was greatly influenced by the AFOC incorporation level (10%-20%). These findings suggested that A. orzae fermentation modifies the nutritional quality of OC, as seen through its positive impact on the growth performance, local and systemic immunity, and intestinal absorptive capacity of Nile tilapia. The recommended dose for dietary AFOC was around 11.

Assessment of the effect of platelet rich plasma on the healing of operated sacrococcygeal pilonidal sinus by lay-open technique: a randomized clinical trial.

BACKGROUND: Sacrococcygeal pilonidal sinus disease (PSD) is an infection of the skin and subcutaneous tissue at the upper part of the natal cleft of the buttocks. Excision and healing by granulation "lay-open" method is still more preferable than other methods of midline closure or using flaps but the healing time is lengthy. The present study was performed to assess the healing promotion effect of platelet-rich plasma (PRP) on the pilonidal sinus wounds treated by the lay-open method. METHODS: One hundred patients suffering from PSD were randomly divided into two groups, they were treated by the lay-open method, at General surgery department, Kafr El-Sheik University hospital, Egypt, during the period from December 2018 to December 2019. Group (A) was adopted the regular dressing postoperatively, while group (B) was treated with PRP injection into the wound at 4 and 12 postoperative days. RESULTS: Accelerated rate of wound healing was detected in group (B) in day 10, with a significant difference detected in days 15, 20, 25 and 30 postoperative, with a mean time of complete healing 45 ± 2.6 days in group B, while it was 57 ± 2.4 days in group A with a p-value of 0.001 which indicates considerable effect in the treated group. CONCLUSIONS: PRP injection is an effective new technique in accelerating the healing of pilonidal wound after surgery, with a significant decrease in post-operative pain, complications and an early return to work. TRIAL REGISTRATION: retrospectively registered. TRIAL REGISTRATION NUMBER: 12/35/1016 issued on December 2018 from the Institution Review Board at Kafr El Sheikh University. ClinicalTrials.gov identifier: NCT04430413.

Synthesis, Labeling and Biological Evolution of New Thiopyrano[2,3-b]Pyridine Derivatives as Potential Anticancer Agents.

The new thiopyrano[2,3-b]pyridines 4-9 could be synthesized from the nicotinonitrile derivative 1. The cytotoxicity activity of the selected compounds 5, 6 and 8 was tested against MCF-7 and HCT-116 cell lines. The compound 5 (TP5) exhibited significant inhibitory activity and displayed the most potent activity, more than 6 and 8. The compound 5 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent. In the light of this result, the labeled 125I-compound 5 (125I-TP5) was prepared and its cytotoxicity against ascites tumor in mice has been evaluated. The results show that compound 5 (TP5) may be potentially used as a radiopharmaceutical for tumor diagnosis when labeled with 125I.

Synthesis, preclinical, and pharmacokinetic evaluation of a new zoledronate derivative as a promising antiosteoporotic candidate using radiolabeling technique.

A novel zoledronic acid (ZL) derivative, 3-(2-ethyl-4-methyi-1H-imidazole-1-yl)-1-hydroxy-1-phosphonopropyl phosphonic acid (EMIHPBP), was synthesized, characterized, and successfully radiolabeled with 99m Tc. The in vivo biodistribution of 99m Tc-EMIHPBP was investigated and compared with the previously reported zoledronate derivatives aiming to formulate a novel zoledronate derivative with a high-potential uptake to bone as a promising antiosteoporotic candidate. To further evaluate the bone uptake efficiency, the pharmacokinetics of 99m Tc-EMIHPBP was investigated and showed that maximum concentration in bone (Cmax ) was 31.60 ± 0.15%ID/gram after 60 minutes (tmax ). Cumulative residence of 99m Tc-EMIHPBP in the bone [AUC (0-∞) (%ID∙min/gram bone)] was 3685.23, mean residence time was 384.354 minutes, and the calculated bone bioavailability was 15.831%. Finally, the time needed for half of the 99m Tc-EMIHPBP formulation to be eliminated from bone (t1/2 ) was 263.914 minutes. Excellent bone uptake can be obtained 1-hour postinjection with high bone/blood ratio of 23.76 detected with gamma counter. The biodistribution and kinetic studies could recommend EMIHPBP as a promising antiosteoporotic candidate with high selectivity to the skeletal system and rapid clearance from soft tissues.

Preparation of (99m)tc-clomiphene citrate as a novel agent for breast cancer imaging.

The aim of this work was to develop a novel (99m)Tc-labelled derivative based on triphenylethylene for breast cancer imaging. (99m)Tc-Clomiphene was obtained with a radiochemical yield of 94.4% by adding (99m)Tc to 1.5 mg Clomiphene citrate in the presence of 10 µg SnCl(2) at pH 7. The optimization of the labeling yield of Clomiphene citrate, with (99m)Tc, is described. The reaction parameters that affect the labeling yield were studied to optimize the labeling conditions. Radiochemical purity of the final product has been verified by means of paper chromatography and paper electrophoresis. Ehrlich Ascites Carcinoma (EAC) as a model of breast cancer cells was injected intraperitoneally (IP) to produce ascites and intramuscularly (IM) to produce solid tumor. Biodistribution study was carried out by the injecting solution of (99m)Tc-Clomiphene in normal and tumor bearing mice. The uptake in ascites was over 12.5 % injected dose per gram tissue body weight, at 1hr after injection and above 12% in solid tumor. The T/NT value for (99m)Tc-Clomiphene complex was found to be 5.5 ± 0.4 which was higher than that of the commercially available (99m)Tc-MIBI. This data revealed the localization of tracer in tumor tissue with high percent sufficient to use (99m)Tc-Clomiphene as a promising tool for the diagnosis of breast cancer.

Prognostic factors predicting successful response to sildenafil after radical cystoprostatectomy.

OBJECTIVES: To assess the efficacy and safety of sildenafil citrate in the management of erectile dysfunction (ED) following radical cystectomy (RC) and to define the different prognostic factors predicting the response to sildenafil in such a challenging group of patients. MATERIAL AND METHODS: One hundred patients with ED following RC participated in an open-label, non-randomized, prospective, dose-escalation study. The median age of the patients was 53 years and the mean period after RC was 80.7 +/- 54.8 months. The study duration was 12 weeks, comprising a 4-week run-in period followed by two active treatment periods of 4 weeks each with 50 and 100 mg of sildenafil. Patients were assessed by means of the International Index of Erectile Function (IIEF) questionnaire at baseline and after each treatment period. At the end of the study, the Global Efficacy Assessment Question was used to evaluate treatment satisfaction. Factors affecting the patient's response to sildenafil were assessed by means of uni- and multivariate analysis. RESULTS: The entire study group was suffering from severe ED at baseline, with a mean erectile function (EF) domain score of 6.5 +/- 0.93. EF scores improved to 12.2 +/- 7.76 and 18 +/- 10.3 with 50 and 100 mg of sildenafil, respectively. Sildenafil therapy significantly improved the ability of many patients to achieve and maintain an erection. The mean scores for question 3 of the IIEF were 1 +/- 0.14, 2.1 +/- 1.4 and 3 +/- 1.8 at baseline and with 50 and 100 mg of sildenafil, respectively, while the corresponding scores for question 4 were 1 +/- 0.10, 1.9 +/- 1.35 and 3 +/- 1.85. The satisfaction rate was 54%. The response was dose-dependent but the incidence of adverse effects increased from 6% with 50 mg of sildenafil to 34% with 100 mg. In univariate analysis, tumor histology and grade and postoperative partial tumescence were found to significantly impact the patient's response to sildenafil. In multivariate analysis, postoperative partial tumescence was the only independent predictive variable. CONCLUSIONS. Sildenafil was found to be a safe and satisfactory treatment for post-RC ED. The effect was dose-related. Patients with postoperative partial tumescence were the best responders.