In vivo testing of novel nitric oxide-releasing nanoparticles for alleviating heart failure using the zebrafish embryo model.

Heart failure (HF) is a multifactorial, heterogeneous systemic disease that is considered one of the leading causes of death and morbidity worldwide. It is well-known that endothelial dysfunction (ED) plays an important role in cardiac disease etiology. A reduction in the bioavailability of nitric oxide (NO) in the bloodstream leads to vasoconstriction and ED. Many studies indicated diminishment of peripheral arteries vasodilation that is mediated by the endothelium in the of patients with chronic HF. With the advancement of nanomedicine, nanotechnology can provide adequate solutions for delivering exogenous NO with the aid of nanoparticles (NPs) to treat ED. The properties of superparamagnetic iron oxide nanoparticles (SPIONs) enable both passive and active delivery of drugs. This prompted us to investigate the efficacy of our newly-developed hydrogel nanoparticles (NO-RPs) for the delivery and sustained release of NO gas to alleviate cardiac failure and inflammation in the heart failure zebrafish model. The hydrogel NO-RPs incorporate SPIONS and NO precursor. The sustainend release of NO in the NO-RPs (4200 s), overcomes the problem of the short half life of NO in vivo which is expected to ameliorate the reduced NO bioavailabilty, and its consequences in endothelial and cardiac dysfunction. Zebrafish embryos were used as the animal model in this study to determine the effect of SPIONs-loaded NO-RPs on the cardiovascular system. Cardiac failure was induced in 24hpf embryos by exposure to aristolochic acid (AA)(0.25, 0.5 µM) for 8 h, followed by the SPIONs-loaded NO-RPs (0.25, 0.5 mg/ml) for 48 h, experimental groups included: control group which is healthy non treated zebrafish embryos, AA injured zebrafish embryos (HF) model,and NO-RP treated HF zebrafish embryos. Survival rate was assessed at 72hpf. Cardiac function was also evaluated by analyzing cardiac parameters including heartbeat, major blood vessels primordial cardinal vein and dorsal aorta (PCV &DA) diameter, blood flow velocity in PCV & DA vessels, cardiac output, and PCV & DA shear stresses. All cardiac parameters were analyzed with the aid of MicroZebraLab blood flow analysis software from Viewpoint. In addition, we studied the molecular effects of the developed NO-RPs on the mRNA expression of selected pro-inflammatory markers: IL-6, and Cox-2. Our findings demonstrated that the NO-RPs improved the survival rate in the heart failure zebrafish model and reversed heart failure by enhancing blood flow perfusion in Zebrafish embryos, significantly. In addition, RT-PCR results showed that the NO-RPs significantly reduced the expression of pro-inflammatory markers (lL-6&COX-2) in the heart failure zebrafish model. Our study confirmed that the developed SPIONs-loaded NO-RPs are effective tool to alleviate cardiac failure and inflammation in the HF zebrafish model.

Exploiting itraconazole-loaded nanomixed micelles in coated capsules as efficient colon-targeted delivery system for improved antifungal and potential anticancer efficacy.

Chronic Inflammatory bowel diseases are usually accompanied by opportunistic colonic fungal infections. Itraconazole (ITZ), is a highly lipophilic broad-spectrum antifungal drug that is superiorly effective against several fungal species. Box-Behnken design was adopted to design ITZ-nanomixed micelles (ITZ-NMMs), aiming to enhance ITZ solubility, using various concentrations of Pluronic® L121, Cremophor EL, and with either sodium-deoxycholate or Pluronic® F68 through thin film hydration technique. Optimized formula composed of 90 % Pl-L121, 9.1% Cremophor EL, 3.127 % ITZ concentration and SDC as the hydrophilic surfactant and its particle size, Polydispersity index, zeta potential, entrapment efficiency, and release extent after 3 h were found to be 17.82 ± 0.189 nm, 0.26 ± 0.014, -6.72 ± 0.725 mV, 66 ± 7.4%, and 96.3 ± 7.22%, respectively. In vitro ITZ release study implied the ability of optimal ITZ-NMMs to enhance ITZ solubility in comparison to ITZ suspension. Also, augmented anti-fungal and anti-cancer activities were proven as ITZ-NMMs IC50 was 16.5 times that of pure ITZ. Afterwards, lyophilized optimal ITZ-NMMs formula was loaded into Eudragit S100-coated capsules where in vitro release and in vivo X-ray imaging ensured protection of ITZ release in either the stomach or intestine and targeting it to the colon. Such results suggested promising ITZ-NMMs system, capable of enhancing ITZ solubility in the intended target site, therefore, can be used not only in the treatment of colon fungal infections but also augments colon cancer therapy.

Biochemical study on modifying role of variants of leptin gene and its receptor on serum leptin levels in breast cancer.

The leptin is discharged from breast adipose tissue and is overexpressed in breast cancer (BC). Conflicting relation of leptin with BC was reported. We investigated this association and its impact on leptin level and disease characteristics. The study included 70 females (40 women with pathological proof of invasive BC patients and 30 controls). LEP and LEPR polymorphisms were evaluated by real-time PCR. Serum leptin was estimated by ELISA. Both LEPR and LEP disturbances increase the danger of BC where GG genotype and G allele frequencies of LEPR were higher in patients vs. control. GG genotype increases BC risk with OR (9.1) while G allele predisposes to disease with OR (3.8). Furthermore, LEP A allele was uniquely elevated in patients than healthy ones with OR (2.06). Precise relation of circulating leptin and its polymorphisms with predicting BC may authorize its utilization in early screening.

Metformin hydrochloride and wound healing: from nanoformulation to pharmacological evaluation.

Niosomes as drug delivery systems have the ability to decrease drugs' side effects and increase their therapeutic effectiveness. Metformin HCl is an oral antihyperglycemic agent belonging to biguanides. It is the most commonly chosen drug as a startup therapy for patients newly diagnosed with type 2 diabetes. This study aims to encapsulate metformin HCl inside niosomes to be used as a transdermal formulation helping to prolong its antidiabetic effect and investigate its ability to enhance wound healing in diabetic patients. Thin film hydration method was used to prepare metformin HCl niosomes using different proportions of Span 60, Span 40, Tween 80, and cholesterol. All formulations were characterized using transmission electron microscope, zeta potential, and vesicle size. In vitro release studies, stability studies and in vivo evaluation were conducted on selected niosomal formulations. The results of entrapment efficiency ranged from 13% to 32%. Vesicle sizes were determined in nano-range. The in vitro release profile of metformin HCl from niosomes occurred in two consecutive phases. Biological evaluation on diabetic rats revealed that metformin HCl niosomal gel given every 2 days showed a better sustained antidiabetic effect than oral doses given daily. It also showed an improvement in wound healing for diabetic rats given metformin formulations compared to nontreated ones.

Real time stability and viability prediction of the anticancer BCG after lyophilization.

To test if trehalose could be a better cryoprotectant for BCG than the usually used lactose and predict viability of BCG during shelf-life, BCG was suspended into three stabilizer systems containing 15% w/v trehalose, trehalose-gelatin mixture (in ratio, 30:1 w/w) or lactose. Each formula was lyophilized and several quality parameters were tested before and after lyophilization including sterility, safety, viability, morphology and moisture content. Samples of lyophilized formulae were tested for their reconstitution time and others were charged to stability chambers at 5°C for the performance of real time study. Shelf-life of each formula was estimated and correlation between moisture content and loss in viability was established at each time interval of the real time stability study. Sterility, safety and morphology were retained after lyophilization. Just after lyophilization, minute diminish in viability was observed in the presence of each stabilizer (0.02-0.05%). There was no significant difference in reconstitution time of the three lyophilized formulae. Lactose BCG had the highest shelf-life among the used cryoprotectants during the real time stability studies. Also, moisture content was highly correlated to viability with correlation coefficient ranged between 0.97 and 0.99 and so, the former could be used for prediction of viability throughout the vaccine shelf-life.

Ocular Mucoadhesive and Biodegradable Sponge-Like Inserts for the Sustained and Controlled Delivery of Voriconazole; Preparation, D-optimal Factorial Optimization and in-vivo Evaluation.

The aim of this study was to formulate and optimize by statistical means mucoadhesive and biodegradable sponge-like inserts loaded with voriconazole (VCZ) which increases the contact time of the drug with the eye and sustain its release from the formula in a controlled manner. This avoids the pulsed effect reported for the drug suspension and results in reducing the number of drug instillations in the eye with the result of enhancing the patient compliance. Also, the sponge like nature of the insert reduces the foreign body sensation caused by other ocular solid dosage forms. They were prepared using casting/freeze-drying technique using five polymers namely high molecular weight chitosan (CH), sodium alginate (AL), sodium carboxy methyl cellulose (CMC), gellan gum (GG) and xanthan gum (XG). The prepared inserts were subjected to evaluations of their visual appearance, weight variation, drug content, surface pH, in-vitro release (percent drug released after 1h (Q1 (%)), mean dissolution time (MDT) and dissolution efficiency (DE)) in addition to kinetic analysis of the release data, water uptake, mucoadhesion and rheology of the forming plain polymer solution at the maximum rate of shear. The independent variables of the D-optimal factorial design were the polymer type and concentration while Q1 (%), MDT, DE, % water uptake after 15 minutes and rheology at the maximum rate of shear were chosen as dependant variables. The performed optimization process using design expert software showed an optimum formula consisting of 2 % GG. It showed slow release behavior compared to the drug suspension. FTIR and DSC studies showed that there is no interaction between VCZ and GG. The optimum formula has good in-vitro mucoadhesive properties and pH in the safe ocular range. Moreover, it showed promising in-vivo results of rapid hydration and gelling in addition to good mucoadhesive behavior when instilled in the eye, high ocular safety and biocompatibility, sustained antifungal activity in comparison to the drug suspension and finally biodegradation. So, it may be taken into consideration as an outstanding carrier for the ocular delivery of VCZ.

Renal arterial resistive index versus novel biomarkers for the early prediction of sepsis-associated acute kidney injury.

Acute kidney injury (AKI) is a critical complication of sepsis. There is a continuous need to identify and validate biomarkers for early detection. Serum and urinary biomarkers have been investigated, such as neutrophil gelatinase associated lipocalin (NGAL) and cystatin C (Cys C), but their reliability in the intensive care unit (ICU) remains unknown. Renal hemodynamics can be investigated by measuring the renal resistive index (RRI). This study aimed to compare the performance of RRI, serum NGAL (sNGAL), urinary NGAL (uNGAL), and serum Cys C levels as early predictors of the diagnosis and persistence of sepsis-associated AKI. A total of 166 adult patients with sepsis syndrome were enrolled immediately after ICU admission. Biomarkers were measured directly (T1) and on day 3 (T3). RRI was measured directly (T1) and 24 h later (T2). Patients were categorized (according to the occurrence and persistence of AKI within the first 7 days) into three groups: no AKI, transient AKI, and persistent AKI. The incidence rate of sepsis-associated AKI was 60.2%. Sixty-six patients were categorized as in the no AKI group, while another 61 were in transient AKI and only 39 were in persistent AKI. The RRI value (T1 ≥ 0.72) was the best tool for predicting AKI diagnosis (area under the receiver operating characteristic curve, AUROC = 0.905). Cys C (T1 ≥ 15.1 mg/l) was the best tool to predict the persistence of AKI (AUROC = 0.977). RRI (T1) was the best predictive tool for sepsis-associated AKI, while Cys C was the best predictor of its persistence and 28-day mortality.

Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization.

CONTEXT: Buspirone HCl has very low oral bioavailability (4%) due to deactivation by extensive first pass effect. It also has very limited transdermal permeation due to its high hydrophilicity. OBJECTIVE: The aim of this study was to increase the transdermal permeation of buspirone HCl utilizing a stable dosage form. METHODS: Transfersomes were prepared using Tween-80 as a flexibility imparting agent to the vesicular walls. Oleic acid and/or ethanol, with different percentages, were utilized as a permeation enhancer. Formulations were characterized by analyzing particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release and ex vivo drug permeation. Factorial design (3(2)) was planned for the optimization of formulations using Design-Expert® software. Lyophilized transfersomal gel of the optimized formulation was prepared using hydroxypropyl methylcellulose (HPMC) K100, carboxymethyl cellulose or sodium alginate with or without mannitol as a cryoprotectant. Physical characterization of the transfersomes and the lyophilized gel were carried out using transmission and scanning electron microscopy, respectively. RESULTS: The optimized formulation (T7), containing 35% oleic acid, had the highest desirability value (0.658) with high ex vivo drug flux (43.40 µg/h/cm(2)) through rat skin when compared with the aqueous drug solution and formula T1 (without oleic acid). The T7 transfersomal gel containing HPMC K100 (G2) had the highest desirability value (0.640) among the lyophilized gel formulations with decreased ex vivo drug flux (38.98 µg/h/cm(2)) in comparison with the original transfersomal formula (T7). CONCLUSIONS: Lyophilized transfersomal gel containing oleic acid was considered as a promising transdermal delivery system for hydrophilic drugs.

Fabrication and optimization of itraconazole-loaded zein-based nanoparticles in coated capsules as a promising colon-targeting approach pursuing opportunistic fungal infections.

Itraconazole (ITZ), a broad-spectrum antifungal drug, was formulated into colon-targeting system aiming to treat opportunistic colonic fungal infections that commonly infect chronic inflammatory bowel diseases (IBD) patients due to immunosuppressive therapy. Antisolvent precipitation technique was employed to formulate ITZ-loaded zein nanoparticles (ITZ-ZNPs) using various zein: drug and aqueous:organic phase ratios. Central composite face-centered design (CCFD) was used for statistical analysis and optimization. The optimized formulation was composed of 5.5:1 zein:drug ratio and 9.5:1 aqueous:organic phase ratio with its observed particle size, polydispersity index, zeta potential, and entrapment efficiency of 208 ± 4.29 nm, 0.35 ± 0.04, 35.7 ± 1.65 mV, and 66.78 ± 3.89%, respectively. ITZ-ZNPs were imaged by TEM that revealed spherical core-shell structure, and DSC proved ITZ transformation from crystalline to amorphous form. FT-IR showed coupling of zein NH group with ITZ carbonyl group without affecting ITZ antifungal activity as confirmed by antifungal activity test that showed enhanced activity of ITZ-ZNPs over the pure drug. Histopathological examination and cytotoxicity tests ensured biosafety and tolerance of ITZ-ZNPs to the colon tissue. The optimized formulation was then loaded into Eudragit S100-coated capsules and both in vitro release and in vivo X-ray imaging confirmed the success of such coated capsules in protecting ITZ from the release in stomach and intestine while targeting ITZ to the colon. The study proved that ITZ-ZNPs is promising and safe nanoparticulate system that can protect ITZ throughout the GIT and targeting its release to the colon with effectual focused local action for the treatment of colon fungal infections.

Development of Transdermal Oleogel Containing Olmesartan Medoxomil: Statistical Optimization and Pharmacological Evaluation.

Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM.

Development and validation of a risk prediction nomogram for serious arrhythmias in acute digoxin toxicity among pediatrics: A multicenter study.

Digoxin is a cardiac glycoside obtained from the leaves of the foxglove plant, Digitalis lanata. Several studies have described the safety of digoxin including various life-threatening events, notably cardiac arrhythmias. Early identification of high-risk patients and subsequent initiation of the utmost medical care are associated with a better prognosis. The assessment of serum digoxin levels, which is not always convenient, is the only tool used to evaluate the severity of digoxin exposure. However, the feasibility of this tool, particularly in resource-restricted countries, remains unclear. Therefore, the current study aimed to establish and validate a feasible alternative tool, a bedside nomogram, to identify pediatric patients diagnosed with acute digoxin intoxication who are at risk of developing serious arrhythmias. This was a two-phase, multicenter, retrospective study. The prevalence of serious arrhythmias was approximately 17%. Patients diagnosed with serious arrhythmias showed significantly higher serum digoxin, random blood glucose, and potassium levels but lower sodium, magnesium, and hemoglobin levels. Serious arrhythmias were associated with significantly lower P-R intervals, shorter QTc intervals, and more frequent digoxin effects (p < 0.05). The proposed nomogram showed that combining age and initial random blood glucose, sodium, and potassium levels could predict the future incidence of serious arrhythmia with an accuracy of 96.2% (sensitivity = 94.4%, specificity = 96.5%), an area under the curve (AUC) of 0.977, and p < 0.001. Validation of the proposed nomogram yielded an AUC for the nomogram probability of approximately 81%, and the AUC for the predicted probability using the developed model was 98.3%, indicating that both the validated model and the developed nomogram were significant predictors of serious arrhythmia. The utility of using the four-factor nomogram to determine the risk of serious arrhythmia in children exposed to an overdose of digoxin is comparable, if not superior, to the serum digoxin level.

A novel injectable in situ forming poly-DL-lactide and DL-lactide/glycolide implant containing lipospheres for controlled drug delivery.

One of the greatest challenges in in situ forming implant (ISFI) systems by polymer precipitation is the large burst release during the first 1-24 hours after implant injection. The aim of this study was to decrease the burst-release effect of a water-soluble model drug, donepezil HCl, with a molecular weight of 415.96 Da, from in situ forming implants using a novel in situ implant containing lipospheres (ISILs). In situ implant suspensions were prepared by dispersing cetyl alcohol and glyceryl stearate lipospheres in a solution of poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG). Also, in situ implant solutions were prepared using different concentrations of PDL or PDLG solutions in N-methyl-2-pyrrolidone (NMP). Triacetin and Pluronic L121 were used to modify the release pattern of donepezil from the in situ implant solutions. In vitro release, rheological measurement, and injectability measurement were used to evaluate the prepared in situ implant formulae. It was found that ISIL decreased the burst effect as well as the rate and extent of drug release, compared to lipospheres, PDL, and PDLG in situ implant. The amount of drug released in the first day was 37.75, 34.99, 48.57, 76.3, and 84.82% for ISIL in 20% PDL (IL-1), ISIL in 20% PDLG (IL-2), lipospheres (L), 20% PDL ISFI (I5), and 20% PDLG ISFI (I8), respectively. The prepared systems showed Newtonian flow behavior. ISIL (IL-1 and IL-2) had a flow rate of 1.94 and 1.40 mL/min, respectively. This study shows the potential of using in situ implants containing lipospheres in controlling the burst effect of ISFI.

Evaluation of Pediatric Early Warning System and Drooling Reluctance Oropharynx Others Leukocytosis scores as prognostic tools for pediatric caustic ingestion: a two-center, cross-sectional study.

Caustic chemicals are widely distributed in our environment. Exposure to caustic agents is a lifelong problem associated with severe tissue and mucous membrane injuries. In pediatrics, corrosive exposure is the most common cause of nonpharmaceutical exposure presenting to poison control centers. Therefore, this study evaluated the role of the Pediatric Early Warning System (PEWS) and Drooling Reluctance Oropharynx Others Leukocytosis (DROOL) scores as early in-hospital outcome predictors following corrosive ingestion. The current study was a two-center, retrospective, cross-sectional study carried out among pediatric patients diagnosed with acute caustic ingestion during the past 4 years. Most exposure occurred accidentally among boys (59.4%) living in rural areas (51.9%) of preschool age (50% were 2-4 years old). Residence, body temperature, respiratory rate, vomiting, skin and mucosal burns, retrosternal pain, respiratory distress, Oxygen (O2) saturation, Glasgow Coma Scale score, HCO3 level, total bilirubin level, anemia, leukocytosis, and presence of free peritoneal fluid were significant predictors of esophageal injuries (p < 0.05). DROOL and PEWS scoring were the most significant predictors of esophageal injuries with worthy predictive power, where odds ratio (95% confidence interval (CI)) was 1.76 (0.97-3.17) and 0.47 (0.21-0.99) for PEWS and DROOL, respectively. At a cutoff of < 6.5, the DROOL score could predict esophageal injuries excellently, with AUC = 0.931; sensitivity, 91.7%; specificity, 72.5%; and overall accuracy, 91.3%. At a cutoff of > 6.5, PEWS could significantly predict unfavorable outcomes, with AUC = 0.893; sensitivity, 94.4%; specificity, 71.9%; and overall accuracy, 89.3%. However, PEWS better predicted the need for admittance to the intensive care unit (ICU). Pediatric Early Warning System (PEWS) and Drooling Reluctance Oropharynx Others Leukocytosis (DROOL) are potentially useful accurate scorings that could predict the esophageal injuries and ICU admission following corrosive ingestion in pediatrics.

Simultaneous Optimization of Oral and Transdermal Nanovesicles for Bioavailability Enhancement of Ivabradine Hydrochloride.

PURPOSE: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most ß-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally. MATERIALS AND METHODS: A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics. RESULTS: The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, -40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively. CONCLUSION: Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.

In Situ-Forming Microparticles for Controlled Release of Rivastigmine: In Vitro Optimization and In Vivo Evaluation.

In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.

Socioeconomic Risk Factors for Preterm Birth in the state of Qatar: A Population-based Study.

OBJECTIVES: To review the demographics and socioeconomic determinants of preterm birth (PTB) compared to term births among the Qatari population. METHODS: This was a retrospective data analysis of 59,308 births. Data were retrieved from a Population-based Cohort Study. Data were gathered from the PEARL-Peristat maternal newborn registry for 2011, 2012, 2017, and 2018. We compared the preterm births group (delivery < 37 weeks) with the term group (delivery ≥ 37 weeks) regarding socioeconomic factors, including maternal nationality, religion, level of education, mother's occupation, family income, housing, consanguinity, early childbearing, high-risk pregnancy, smoking, assisted conception, antenatal care, and place of delivery. RESULTS: The prevalence of preterm birth was 9%. There were more Saudi nations in the preterm group compared to term (33% vs. 28%, p-value < 0.001). There were more preterm births than term births among working mothers (40% vs. 35%), high-risk pregnancies (24% vs. 18%), those that has used assisted conception (18% vs. 3%), those without antenatal care (11% vs. 5.6%), and those delivered in a tertiary women hospital (88.5% vs. 84.5%) (all p-values < 0.001). There were more women living in villas (41% vs. 38%, p = 0.01) and more smokers (0.8% vs. 0.5%, p = 0.030) in the preterm group than in the term group. There were no differences between the two groups regarding religion, level of maternal education, family income, and early childbearing. CONCLUSION: In our population, we identified several factors associated with preterm births, the most important is Lack of antenatal care , assisted conception and working mothers.

Colossolactone-G synergizes the anticancer properties of 5-fluorouracil and gemcitabine against colorectal cancer cells.

Several terpenoids were isolated from Ganoderma colossum with potential chemotherapeutic properties against different solid tumor cells. Herein, we further assessed the potential chemomodulatory effects of colossolactone-G to gemcitabine (GCB) and 5-fluorouracil (5-FU) against colorectal cancer cells. Colossolactone-G induced moderate cell killing effects against both HT-29 and HCT-116 cells, with IC50's of 90.5 ± 1.7 µM and 22.3 ± 3.9 µM, respectively. Equitoxic combination demonstrated a synergistic effect between colossolactone-G and GCB, or 5-FU with combination indices ranging from 0.22 to 0.67. Both GCB and 5-FU induced moderate cell cycle arrest at G0/G1-phase and S-phase. Despite colossolactone-G's lack of influence on cell cycle distribution, it significantly potentiated GCB- and 5-FU-induced cell cycle arrest. Similarly, colossolactone-G treatment alone did not induce pronounced apoptosis in both cell lines. However, 5-FU and GCB induced significant apoptosis which was further potentiated via combination with colossolactone-G. Furthermore, colossolactone-G significantly increased autophagic cell death response in both HCT-116 and HT-29 cells and potentiated 5-FU- and GCB-induced autophagic cell death. The influence of colossolactone-G alone or in combination with GCB or 5-FU on the apoptosis and autophagy were confirmed by qPCR analysis for the expression of several key apoptosis and autophagy genes such as, TRAIL, TP53INP1, BNIP3, hp62, ATG5, ATG7, Lamp2A and the golden standard for autophagy (LC3-II). In conclusion, a synergistic effect in terms of anticancer properties was observed when colossolactone-G was combined with 5-FU and GCB, where it influenced both apoptosis and autophagic cell death mechanisms.

Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.

PURPOSE: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. MATERIALS AND METHODS: Cubo-gels were prepared by 33 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubo-gel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. RESULTS: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. CONCLUSION: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

Molecular docking and statistical optimization of taurocholate-stabilized galactose anchored bilosomes for the enhancement of sofosbuvir absorption and hepatic relative targeting efficiency.

The work aimed to improve both absorption and hepatic availability of sofosbuvir. Bilosomes and galactose-anchored bilosomes were investigated as potential nanocarriers for this purpose. Sofosbuvir is a class III drug with high solubility and low permeability. Thus, the drug entrapment into lipid-based galactose-anchored carriers would enhance drug permeability and improve its liver availability. The galactosylated taurocholate was designed and synthesized based on molecular docking studies, where both galactose and taurocholate molecules were connected in a way to avoid affecting crucial interactions and avoid steric clashes with their cellular uptake receptors. The suggested nano-carriers were prepared using a thin-film hydration technique with sodium taurocholate and span 60 as stabilizers. The prepared formulae were statistically optimized using a central composite design. The optimized plain and galactosylated formulae, composed of SAA to drug ratio of 1:1 w/w and sodium taurocholate to span ratio of 10:1 w/w, have a vesicular size, zeta potential and entrapment efficiency in the range of 140-150 nm, -50 mV and 85%, respectively. The optimized formulae were lyophilized to increase their physical stability and facilitate accurate drug dosing. In vivo results showed that Sofosbuvir availability in the liver was significantly increased after oral administration of the plain and the galactosylated bilosomal formulae when compared to the oral drug solution with relative targeting efficiencies (RTIs) of 1.51 and 3.66, respectively. These findings confirmed the hypothesis of considering the galactosylated bilosomes a promising nanocarrier to efficiently target sofosbuvir to the liver.

Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects.

Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer's disease, Parkinson's disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.