Hatem A. Sarhan

Design, synthesis, antibacterial activity and physicochemical parameters of novel N-4-piperazinyl derivatives of norfloxacin

We report herein the synthesis of some N-Mannich bases in addition to different N-4 substituents of norfloxacin. The antibacterial activities of the newly synthesized compounds were evaluated and correlated with their physicochemical properties. Results revealed that some of the tested compounds exhibited better inhibitory activities than the reference antibiotic norfloxacin against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus strains. Correlation results showed that there is no single physicochemical parameter that can determine the effect of N-4 piperazinyl group on the activity of these fluoroquinolones, where lipophilicity, molecular mass and electronic factors may influence the activity.

Preparation and evaluation of polyamidoamine dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (G3) as a novel carrier for siRNA.

Abstract In this study, we newly synthesized the polyamidoamine STARBURST dendrimer (dendrimer, generation 3: G3) conjugates with 6-O-α-(4-O-α-d-glucuronyl)-d-glucosyl-β-cyclodextrin [GUG-β-CDE (G3)] having the various degrees of substitution (DS) of GUG-β-cyclodextrin of 1.6, 3.0, 3.7, 5.0 and 8.6, and evaluated them as a siRNA transfer carrier. GUG-β-CDEs (G3) formed the positively charged and nano-order complexes with siRNA. Of the siRNA complexes with five GUG-β-CDEs (G3), the complex with GUG-β-CDE (G3, DS 3.7) showed the highest RNAi effect and cellular uptake with negligible cytotoxicity in KB cells at a charge ratio of 20. In addition, the RNAi effect and cellular uptake of the complex with GUG-β-CDE (G3, DS 3.7) were higher than those of α-CDE (G3, DS 2.4) and comparable to those of Lipofectamine™ 2000. Furthermore, the complex with GUG-β-CDE (G3, DS 3.7) possessed the endosomal escaping ability, the releasing property of siRNA in the cytoplasm and serum resistance. These results suggest that GUG-β-CDE (G3, DS 3.7) has the potential as a novel siRNA carrier.

Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor

Abstract The present work aimed to prolong the contact time of flurbiprofen (FBP) in the ocular tissue to improve the drug anti-inflammatory activity. Different niosome systems were fabricated adopting thin-film hydration technique and using the nonionic surfactant Span 60. The morphology of the prepared niosomes was characterized by scanning electron microscopy (SEM). Physical characterization by differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy were conducted for the optimized formula (F5) that was selected on the basis of percent entrapment efficiency, vesicular size and total lipid content. F5 was formulated as 1% w/w Carpobol 934 gel. Pharmacokinetic parameters of FBP were investigated following ocular administration of F5-loaded gel system, F5 niosome dispersion or the corresponding FBP ocular drops to albino rabbits dispersion. Anti-inflamatory effect of F5-loaded carbopol gel was investigated by histopathological examination of the corneal tissue before and after the treatment of inflamed rabbit eye with the system. Results showed that cholesterol content, surfactant type. and total lipid contents had an apparent impact on the vesicle size of the formulated niosomes. Physical characterization revealed reduced drug crystallinity and incidence of interaction with other niosome contents. F5-loaded gel showed higher Cmax, area under the curve (AUC0–12), and thus higher ocular bioavailability than those of the corresponding FBP ocular solution. F5-loaded gel showed a promising rapid anti-inflammatory effect in the inflamed rabbit eye. These findings will eradicate the necessity for frequent ocular drug instillation and thus, improve patient compliance.

Finasteride-loaded biodegradable nanoparticles: Near-infrared quantification of plasma and prostate levels

Finasteride is an orally active testosterone 5-alpha-reductase inhibitor that is used for the treatment of benign prostatic hyperplasia as a surgical alternative. The aim of this work was to improve finasteride levels in plasma and prostate through the formulation of biodegradable finasteride nanoparticles and to quantify finasteride levels using near-infrared application. Finasteride nanoparticles were prepared by emulsion solvent evaporation method utilizing the biodegradable polymers poly(lactic-co-glycolic acid) and poly-ϵ-caprolactone. The prepared nanoparticles were characterized by particle size, zeta potential, and encapsulation efficiency. The selected finasteride-biodegradable formula was examined in vivo, and both plasma and prostate levels of finasteride were quantified utilizing near-infrared technique. Results revealed that the prepared finasteride nanoparticles size range was from 231 ± 78 to 956 ± 224 nm with finasteride–poly-ϵ-caprolactone nanoparticles showing larger particle sizes compared with finasteride–poly(lactic-co-glycolic acid) nanoparticles. The encapsulation efficiency ranged from 68.89% ± 2.99% to 99.15% ± 4.32%. The selected formula of finasteride nanoparticles showed improved levels of finasteride in both plasma and prostate of the investigated rats. The realization of sustained release of biodegradable finasteride nanoparticles for possible oral or parenteral application could improve the activity of the drug for sustaining release time with lower dosing recurrence that improves patient compliance.

Targeted siRNA delivery to tumor cells by folate-PEG-appended dendrimer/glucuronylglucosyl-β-cyclodextrin conjugate

We previously reported the utility of 6-O-α-(4-O-α-d-glucuronyl)-d-glucosyl-β-cyclodextrin (GUG-β-CyD) conjugates with polyamidoamine dendrimer [GUG-β-CDE (generation 3; G3)] as siRNA carriers. In this study, to prepare GUG-β-CDE (G3) possessing a targeting ability to tumor cells overexpressing folate receptor-α (FR-α), we newly synthesized folate-polyethylene glycol (PEG)-appended GUG-β-CDEs (G3) [Fol-PEG-GUG-β-CDEs (G3)] having degrees of substitution of folate (DSF) of 3.9, 6.7 and 7.3, and evaluated their utility as tumor-selective siRNA carriers. Of various Fol-PEG-GUG-β-CDEs (G3), Fol-PEG-GUG-β-CDE (G3, DSF6.7) showed the highest siRNA transfection activity at a charge ratio of 50 (carrier/siRNA) in both 786-0-luc cells [FR-α (+)] and KB cells [FR-α (+)]. In addition, the cellular uptake of the complex was significantly decreased by an addition of folic acid in a concentration-dependent manner, suggesting its FR-α-mediated endocytosis pathway. Moreover, Fol-PEG-GUG-β-CDE (G3, DSF6.7)/siRNA complex induced a potent RNAi effect, comparable to Lipofectamine™ 2000/siRNA complex. Furthermore, Fol-PEG-GUG-β-CDE (G3, DSF6.7) complex with siRNA against Polo-like kinase 1 (siPLK1) showed a significant cytotoxic activity in KB cells. Thus, Fol-PEG-GUG-β-CDE (G3, DSF6.7) has the potential as the targeted siRNA delivery carrier for FR-α-overexpressing tumor cells.

Optimization and Characterization of Thymoquinone-Loaded Liposomes with Enhanced Topical Anti-inflammatory Activity

Thymoquinone, the major constituent of Nigella sativa oil has been found to have a promising topical anti-inflammatory activity; however, exaggerated heat and photo-sensitivity and lipophilicity prevent the best use of this promising product. The present work aimed to formulate an ideal thymoquinone liposomal system for topical delivery. Different liposomal systems were developed using thin film hydration method by applying different cholesterol molar concentrations, different total lipid molar concentrations, and different drug-to-lipid ratios. Morphological characterization of the prepared formulae was performed using polarized light, scanning electron microscope, and transmission electron microscope. The optimized formula (F12) was selected on the basis of enhanced permeation through the skin and was incorporated into chitosan gel for topical application. The gel formulation was clear with suitable skin permeation and exhibited acceptable rheological properties. Using carrageenan-induced paw edema in rats, the developed chitosan gel (F12) showed significant superior in vivo anti-inflammatory activity over the chitosan gel of the TQ (p < 0.05) and comparable effect to the marketed indomethacin gel. As a conclusion, results revealed the potential of formulating thymoquinone as liposomal formulation in enhancing the anti-inflammatory effect compared to the TQ solution.

Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules

&NA; Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi‐based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l‐OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA‐lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l‐OHP enhanced the intra‐tumor accumulation of TS shRNA‐lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA‐lipoplex along with the cytotoxic effect of liposomal l‐OHP led to a remarkable tumor growth suppression (compared to mono‐therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti‐cancer agents that can produce a more reliable anti‐tumor effect. Graphical abstract Figure. No caption available.

Extended infusion versus intermittent infusion of imipenem in the treatment of ventilator-associated pneumonia

BACKGROUND Mechanical ventilation support can be the main source of ventilator-associated pneumonia (VAP). VAP is a serious infection that may be associated with dangerous gram-negative bacteria mainly, and it leads to an increase in the mortality in the intensive care unit (ICU). Imipenem is one of the strongest antibiotics now available for treating VAP which is associated with gram-negative and gram-positive bacteria, and it belongs to beta-lactam antibiotic group (carbapenem). OBJECTIVE This study tried to investigate the efficacy of imipenem against VAP when it was infused within 180 min versus the efficacy when it was infused within 30-60 min. SETTING This study was conducted in main ICU in general hospital which consists of surgical and medical beds within 2 years. One hundred and eighty-seven patients were enrolled on it. METHOD This study is a retrospective cohort which was conducted within 2 years. The efficacy of imipenem which was administered by intermittent infusion (30-60 min) within first year was compared with the efficacy of imipenem which was administered by extended infusion (180 min) within second year in the field of VAP curing and cost reduction. All data were collected retrospectively from patient medical files and were statistically analyzed by SPSS version 20. MAIN OUTCOME The study was designed to measure clinical and cost reduction outcomes, mortality and hospital stay. RESULTS The results indicated that there is a significant decrease in mortality, number of recurrent infection, and ICU stay length, and the number of mechanical ventilator days was associated with extended imipenem infusion during the second year of the study. CONCLUSION The use of imipenem with extended infusion over 3 hours enhances its clinical outcomes in the treatment of VAP.