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2021
Kotta, S., H. M. Aldawsari, S. M. Badr-Eldin, N. A. Alhakamy, and S. Md, "Coconut oil-based resveratrol nanoemulsion: Optimization using response surface methodology, stability assessment and pharmacokinetic evaluation.", Food chemistry, vol. 357, pp. 129721, 2021. Abstract

Phytochemicals are widely studied for therapeutic applications and nanostructured delivery systems for phytochemicals are under spotlight. Resveratrol is a promising candidate for neurodegenerative disorders. In the present study, we aimed to formulate nanoemulsion of resveratrol by ultrasonication process using response surface methodology. The effect of both formulation and ultrasonication process factors were studied for the nanoemulsification process using coconut oil, Pluronic-P107, and Cremophor EL. The time, intensity, and power of ultrasonication were selected as process factors. The globule size, PDI, and zeta potential were the responses selected. The concentrations of oil and surfactant and the intensity were found to significantly influence the globule size. The concentration of resveratrol in the optimized nanoemulsion formulation was 2.6442 mg/ml. The in vitro drug release in pH 6.8 phosphate buffer as well as in vitro permeation study on goat nasal mucosa proved the superiority of the nanoemulsion formulation. On intranasal administration in the rat at a resveratrol dose of 2 mg/kg, the brain targeting efficacy of the nanoemulsion formulation was high. Overall, this research provides the benefit of intake of resveratrol containing fruits and, its incorporation into nanoemulsions system could be a promising alternative for the management of Alzheimer's disease.

Badr-Eldin, S. M., N. A. Alhakamy, U. A. Fahmy, O. A. A. Ahmed, H. Z. Asfour, A. A. Althagafi, H. M. Aldawsari, W. Y. Rizg, W. A. Mahdi, A. F. Alghaith, et al., "Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates.", Frontiers in pharmacology, vol. 11, pp. 642171, 2021. Abstract

Fluvastatin (FLV) is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor often used to lower total and low-density lipoprotein (LDL) cholesterol and for the prevention of adverse cardiovascular events. This drug as well as melittin (MEL), the major component of honeybee venom (), has shown antineoplastic activity, then representing promising approaches for cancer therapy. However, adverse effects related to the use of FLV and MEL have been reported and very few studies have been carried out to obtain an optimized formulation allowing for combining the two drugs and then maximizing the anticancer activity, then minimizing the needed dosage. In the present study, an optimized formulation in terms of minimized particle size and maximized zeta potential was investigated for its cytotoxic potential in human OVCAR3 ovarian cancer cells. FLV-MEL nano-conjugates, containing a sub-toxic concentration of drug, demonstrated an improved cytotoxic potential (IC50 = 2.5 µM), about 18-fold lower, compared to the free drug (IC50 = 45.7 µM). Cell cycle analysis studies demonstrated the significant inhibition of the OVCAR3 cells proliferation exerted by FLV-MEL nano-conjugates compared to all the other treatments, with a higher percentage of cells accumulating on G2/M and pre-G1 phases, paralleled by lower percentage of cells in G0/G1 and S phases. The synergistic antineoplastic activity of FLV and MEL combined in the optimized formula was also showed by the marked pronecrotic and pro-apoptotic activities, the latter mediated by the modulation of BAX/BCL-2 ratio in favor of BAX. Our optimized FLV-MEL formulation might therefore represents a novel path for the development of specific and more effective antineoplastic drugs directed against ovarian cancer.

Alhakamy, N. A., M. W. Al-Rabia, S. Md, A. Sirwi, S. S. Khayat, S. S. AlOtaibi, R. A. Hakami, H. Al Sadoun, B. M. Eldakhakhny, W. H. Abdulaal, et al., "Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against .", Pharmaceutics, vol. 13, issue 7, 2021. Abstract

Luliconazole is a new topical imidazole antifungal drug for the treatment of skin infections. It has low solubility and poor skin penetration which limits its therapeutic applications. In order to improve its therapeutic efficacy, spanlastics nanoformulation was developed and optimized using a combined mixture-process variable design (CMPV). The optimized formulation was converted into a hydrogel formula to enhance skin penetration and increase the efficacy in experimental cutaneous infections in Swiss mice wounds. The optimized formulation was generated at percentages of Span and Tween of 48% and 52%, respectively, and a sonication time of 6.6 min. The software predicted that the proposed formulation would achieve a particle size of 50 nm with a desirability of 0.997. The entrapment of luliconazole within the spanlastics carrier showed significant ( < 0.0001) antifungal efficacy in the immunocompromised Candida-infected Swiss mice without causing any irritation, when compared to the luliconazole treated groups. The microscopic observation showed almost complete removal of the fungal colonies on the skin of the infected animals (0.2 ± 0.05 log CFU), whereas the control animals had 0.2 ± 0.05 log CFU. Therefore, luliconazole spanlastics could be an effective formulation with improved topical delivery for antifungal activity against .

Alhakamy, N. A., S. M. Badr-Eldin, W. S. Alharbi, M. A. Alfaleh, O. D. Al-Hejaili, H. M. Aldawsari, B. G. Eid, R. Bakhaidar, F. Drago, F. Caraci, et al., "Development of an Icariin-Loaded Bilosome-Melittin Formulation with Improved Anticancer Activity against Cancerous Pancreatic Cells.", Pharmaceuticals (Basel, Switzerland), vol. 14, issue 12, 2021. Abstract

Pancreatic cancer currently represents a severe issue for the entire world. Therefore, much effort has been made to develop an effective treatment against it. Emerging evidence has shown that icariin, a flavonoid glycoside, is an effective anti-pancreatic cancer drug. Melittin, as a natural active biomolecule, has also shown to possess anticancer activities. In the present study, with the aim to increase its effectiveness against cancerous cells, icariin-loaded bilosome-melittin (ICA-BM) was developed. For the selection of an optimized ICA-BM, an experimental design was implemented, which provided an optimized formulation with a particle size equal to 158.4 nm. After estimation of the release pattern, the anti-pancreatic cancer efficacy of this new formulation was evaluated. The MTT assay was employed for the determination of half maximal inhibitory concentration (IC), providing smaller IC for ICA-BM (2.79 ± 0.2 µM) compared to blank-BM and ICA-Raw (free drug) against PNAC1, a human pancreatic cancer cell line isolated from a pancreatic carcinoma of ductal cell origin. Additionally, cell cycle analysis for ICA-BM demonstrated cell arrest at the S-phase and pre-G1 phase, which indicated a pro-apoptotic behavior of the new developed formulation. The pro-apoptotic and anti-proliferative activity of the optimized ICA-BM against PNAC1 cells was also demonstrated through annexin V staining as well as estimation of caspase-3 and p53 protein levels. It can be concluded that the optimized ICA-BM formulation significantly improved the efficacy of icariin against cancerous pancreatic cells.

Alhakamy, N. A., S. M. Badr-Eldin, H. M. Aldawsari, A. Alfarsi, T. Neamatallah, S. Z. Okbazghi, U. A. Fahmy, O. A. A. Ahmad, B. G. Eid, W. A. Mahdi, et al., "Fluvastatin-Loaded Emulsomes Exhibit Improved Cytotoxic and Apoptosis in Prostate Cancer Cells.", AAPS PharmSciTech, vol. 22, issue 5, pp. 177, 2021. Abstract

Fluvastatin (FLV) is known to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is over-expressed in various cancers. FLV has been reported to decrease cancer development and metastasis. However, because of low bioavailability, extensive first-pass metabolism and short half-life of FLV (1.2 h), it is not appropriate for clinical application. Therefore, FLV-loaded emulsomes were formulated and optimized using Box-Behnken experimental design to achieve higher efficiency of formulation. Antitumor activity of optimized FLV-loaded emulsomes was evaluated in prostate cancer cells using cell cytotoxicity, apoptotic activity, cell cycle analysis, and enzyme-linked immunosorbent assay. The FLV-loaded emulsomes exhibited a monodispersed size distribution with a mean particle size less than 100 nm as measured by zetasizer. The entrapment efficiency was found to be 93.74% with controlled drug release profile. FLV-EMLs showed a significant inhibitory effect on the viability of PC3 cells when compared to the free FLV (P < 0.0025). Furthermore, FLV-EMLs showed significant arrest in G2/M and increase in percentage of apoptotic cells as compared to free FLV. FLV-EMLs were more effective than free FLV in reducing mitochondrial membrane potential and increase in caspase-3 activity. These results suggesting that FLV-EMLs caused cell cycle arrest which clarifies its significant antiproliferative effect compared to the free drug. Therefore, optimized FLV-EMLs may be an effective carrier for FLV in prostate cancer treatment.

El-Shitany, N. A., M. El-Hamamsy, A. A. Alahmadi, B. G. Eid, T. Neamatallah, H. S. Almukadi, R. A. Arab, K. A. Faddladdeen, K. A. Al-Sulami, S. M. Bahshwan, et al., "The Impact of ABO Blood Grouping on COVID-19 Vulnerability and Seriousness: A Retrospective Cross-Sectional Controlled Study among the Arab Community.", International journal of environmental research and public health, vol. 18, issue 1, 2021. Abstract

Studies have noted that some ABO blood types are more susceptible to COVID-19 virus infection. This study aimed to further confirm the relationship between different blood groups on the vulnerability, symptoms, cure period, and severity among COVID-19 recovered patients. This cross-sectional study approached the participants from the Arab community via social media (mainly Facebook and WhatsApp). The data were collected through two Google Form questionnaires, one for COVID-19 recovered patients (COVID-19 group, = 726), and the other for the healthy people (Control group, = 707). The subjects with blood group O were the least likely to be infected with the COVID-19 virus, while those with blood group A were not likely to be the most susceptible. There were significant differences among different ABO blood groups regarding the distribution of oxygen saturation percentage, myalgia, and recovery time after COVID-19 infection ( < 0.01, 0.01, and 0.05, respectively). The blood group A showed the highest percentage of patients who experienced an oxygen saturation range of 90-100%, whereas the blood group O showed the highest percentage of patients who experienced an oxygen saturation range of 70-80%. The blood group A showed the lowest percentage of patients who required artificial respiration, whereas the blood group O showed the highest percentage of patients who required artificial respiration. The blood group B showed the lowest percentage of patients who experienced myalgia and exhibited the lowest percentage of patients who needed 3 weeks or more to recover. The people of blood group O may be the least likely to be infected with COVID-19, however, they may be the more in need of treatment in hospital and artificial respiration compared to the other blood groups.

Aldawsari, H. M., O. A. A. Ahmed, N. A. Alhakamy, T. Neamatallah, U. A. Fahmy, and S. M. Badr-Eldin, "Lipidic Nano-Sized Emulsomes Potentiates the Cytotoxic and Apoptotic Effects of Raloxifene Hydrochloride in MCF-7 Human Breast Cancer Cells: Factorial Analysis and In Vitro Anti-Tumor Activity Assessment.", Pharmaceutics, vol. 13, issue 6, 2021. Abstract

Raloxifene hydrochloride (RLX), an antiosteoporotic agent, has been utilized for guarding against breast cancer and recently, for the disease management owing to its estrogen antagonist activity. Nevertheless, RLX exhibits poor bioavailability that could be attributed to reduced water solubility and first pass metabolism. To overcome these challenges, this study aimed at formulating and optimizing RLX emulsomes (RLX-EMLs) to enhance the drug antitumor activity. A 43 factorial design was employed for assessing the effect of lipoid: solid lipid ratio and solid lipid type on the emulsomes characteristics. The anticancer potential of the optimized formulation and apoptotic parameters were assessed. Vesicle size, entrapment, and release efficiency were significantly influenced by both variables, while zeta potential was influenced by lipoid: solid lipid at < 0.05. The optimal formulation exhibited vesicle size of 236 ± 8.6 nm, zeta potential of -18.6 ± 0.7 mV, drug entrapment of 98.9 ± 4.9%, and release efficiency of 42.7 ± 1.8%. MTT assay showed concentration-dependent inhibition of MCF-7 cells viability. In addition, cells treated with RLX-EMLs showed significant arrest at G2/M phase associated with significant increase in apoptotic and necrotic cells. The enhanced cytotoxic and anti-proliferative effect of RLX-EMLs relative to raw drug was authenticated through increased Bax/Bcl-2 ratio, caspase-9 activation and depletion of mitochondrial membrane potential.

El-Shitany, N. A., S. Harakeh, S. M. Badr-Eldin, A. M. Bagher, B. Eid, H. Almukadi, B. S. Alghamdi, A. A. Alahmadi, N. A. Hassan, N. Sindi, et al., "Minor to Moderate Side Effects of Pfizer-BioNTech COVID-19 Vaccine Among Saudi Residents: A Retrospective Cross-Sectional Study.", International journal of general medicine, vol. 14, pp. 1389-1401, 2021. Abstract

BACKGROUND: The Pfizer-BioNTech COVID-19 vaccine has recently received emergency approval from the US FDA. The mRNA technology was used to manufacture the Pfizer vaccine; however, as a pioneering technology that has never been used in the manufacture of vaccines, many people have concerns about the vaccine's side effects. Thus, the current study aimed to track the short-term side effects of the vaccine.

METHODS: The information in this study was gathered by a Google Form-questionnaire (online survey). The results included the responses of 455 individuals, all of whom are Saudi Arabia inhabitants. Adverse effects of the vaccine were reported after the first and the second doses.

RESULTS: The most common symptoms were injection site pain, headaches, flu-like symptoms, fever, and tiredness. Less common side effects were a fast heartbeat, whole body aches, difficulty breathing, joint pain, chills, and drowsiness. Rare side effects include Bell's palsy and lymph nodes swelling and tenderness. Flu-like symptoms were more common among those under 60 years of age, while injection site pain was more frequent among recipients who were 60 years and older. The study revealed a significant increase in the number of females who suffered from the vaccine side effects compared to males. Difficulty of breathing was more reported among recipients who had been previously infected with the coronavirus compared to those who had not been previously infected.

CONCLUSION: Most of the side effects reported in this study were consistent with Pfizer's fact sheet for recipients and caregivers. Further studies are required to determine the long-term side effects.

Kotta, S., V. K. A. Shirin, R. Sankar, S. M. Badr-Eldin, H. M. Aldawsari, N. A. Alhakamy, and P. K, "Nutraceuticals for alzheimer's disease", Bioactive Nutraceuticals for Brain Disorders: Nova Science Publishers, Inc., 2021. Abstract

Nutraceuticals are compounds of mainly plant origin and are found applicable for the therapy of a largenumber of diseases. They possess important pharmacological actions such as anti-inflammatory,antioxidant, and neuroprotectiveactivities. Alzheimer's disease (AD) is a neurodegenerative disordermostly found in aged groups and is connected with the amyloid-beta peptide and neurofibrillary tangleformation. Even though many drugs are available for the treatment, a complete cure for this disease isnot yet available. This highlights the importance of dietary and lifestyle habits for disease modification.Many compounds of plant origin have been identified to possess potent activity against the development of AD. These nutraceuticals can play major roles in different stages through different molecular targets of AD both in neuronal as well as biochemical levels. These substances have morethan one mechanism in controlling various signaling pathways in the pathogenesis of AD. The chapter gives a detailed description of nutraceuticals that have been explored to date for their beneficiary role in AD. The intake of these food supplements can provide significant benefits in AD as evidenced by different in vitro and in vivo experiments. The food mentioned in this chapter is a proven remedy against AD. So the inclusion of these agents in the daily diet will produce a positive impact on thisneurodegenerative disease of the elderly

Badr-Eldin, S. M., U. A. Fahmy, H. M. Aldawsari, O. A. A. Ahmed, N. A. Alhakamy, S. Z. Okbazghi, M. A El-Moselhy, A. F. Alghaith, A. Anter, A. I. Matouk, et al., "Optimized Self-Nanoemulsifying Delivery System Based on Plant-Derived Oil Augments Alpha-Lipoic Acid Protective Effects Against Experimentally Induced Gastric Lesions.", Dose-response : a publication of International Hormesis Society, vol. 19, issue 1, pp. 15593258211001259, 2021. Abstract

Peptic ulcer disease is an injury of the alimentary tract that leads to a mucosal defect reaching the submucosa. Alpha-lipoic acid (ALA), a natural potent antioxidant, has been known as a gastroprotective drug yet its low bioavailability may restrict its therapeutic efficacy. This study aimed to formulate and optimize ALA using a self-nanoemulsifying drug delivery system (SNEDDS) with a size of nano-range, enhancing its absorption and augmenting its gastric ulcer protection efficacy. Three SNEDDS components were selected as the design factors: the concentrations of the pumpkin oil (X1, 10-30%), the surfactant tween 80 (X2, 20-50%), and the co-surfactant polyethylene glycol 200 (X3, 30-60%). The experimental design for the proposed mixture produced 16 formulations with varying ALA-SNEDDS formulation component percentages. The optimized ALA-SNEDDS formula was investigated for gastric ulcer protective effects by evaluating the ulcer index and by the determination of gastric mucosa oxidative stress parameters. Results revealed that optimized ALA-SNEDDS achieved significant improvement in gastric ulcer index in comparison with raw ALA. Histopathological findings confirmed the protective effect of the formulated optimized ALASNEDDS in comparison with raw ALA. These findings suggest that formulation of ALA in SNEDDS form would be more effective in gastric ulcer protection compared to pure ALA.

Badr-Eldin, S. M., H. M. Aldawsari, O. A. A. Ahmed, N. A. Alhakamy, T. Neamatallah, S. Z. Okbazghi, and U. A. Fahmy, "Optimized semisolid self-nanoemulsifying system based on glyceryl behenate: A potential nanoplatform for enhancing antitumor activity of raloxifene hydrochloride in MCF-7 human breast cancer cells.", International journal of pharmaceutics, vol. 600, pp. 120493, 2021. Abstract

Raloxifene hydrochloride (RLX) is a selective estrogen receptor modulator used for treatment and protection against postmenopausal osteoporosis. The drug has been used for protection against breast cancer and more recently, for management of the disease by virtue of its estrogen antagonist action. However, the drug has reduced bioavailability related to low water solubility and first pass metabolism. To surmount these pitfalls, this study aimed at developing and optimizing RLX-loaded semisolid self-nanoemulsifying system (SSNES) with minimized globule size to improve the drug solubility, tumor penetration, and consequently antitumor activity. A simplex lattice mixture design was employed for the formulation and optimization of SSNESs. The mixture components, namely, Compritol® 888 ATO, Tween 20, and polyethylene glycol 200 exhibited significant effect on globule size at P < 0.05. The optimized formulation with globule size of 109.19 ± 2.11 nm showed acceptable thermodynamic stability under stress conditions. Anti-cancer efficacy of the obtained formulation was evaluated in MCF-7 breast cancer cell line. MTT viability assay revealed that RLX-loaded SSNES notably inhibited MCF-7 cell proliferation. Flow cytometry and dual staining with annexin V-FITC/PI were used to assay this anti-proliferative effect and induction of apoptosis, respectively. Cells treated with RLX-loaded SSNES showed significant arrest at G2/M phase associated with significant increase in early/late-stages of apoptotic and necrotic cells. The results exhibited that RLX-loaded SSNES induces apoptosis via the activation of caspase-3 and loss of mitochondrial membrane potential. Accordingly, the proposed SSNES could be regarded as a promising platform for enhancing RLX antitumor activity against breast cancer.

Alhakamy, N. A., G. Caruso, M. W. Al-Rabia, S. M. Badr-Eldin, H. M. Aldawsari, H. Z. Asfour, S. Alshehri, S. H. Alzaharani, M. M. Alhamdan, W. Y. Rizg, et al., "Piceatannol-Loaded Bilosome-Stabilized Zein Protein Exhibits Enhanced Cytostatic and Apoptotic Activities in Lung Cancer Cells.", Pharmaceutics, vol. 13, issue 5, 2021. Abstract

Piceatannol (PIC) is a naturally occurring polyphenolic stilbene, and it has pleiotropic pharmacological properties. Moreover, PIC has cytotoxic actions among various cancer cells. In this work, preparations of PIC-loaded bilosome-zein (PIC-BZ) were designed, formulated, and characterized, and the optimized PIC-BZ cytotoxic activities, measured as half maximal inhibitory concentration (IC), against lung cancer cell line was investigated. Box-Behnken design was utilized in order to examine the effect of preparation factors on drug entrapment and particle size. PIC-BZ showed a spherical shape after optimization, and its particle size was determined as 157.45 ± 1.62 nm. Moreover, the efficiency of drug entrapment was found as 93.14 ± 2.15%. The cytotoxic activity evaluation revealed that the adjusted formulation, which is PIC-BZ formula, showed a substantially smaller IC versus A549 cells. Cell cycle analysis showed accumulation of cells in the G2-M phase. Moreover, it showed in the sub-G1 phase, a rise of cell fraction suggestion apoptotic improving activity. Increased early and late phases of apoptosis were demonstrated by staining of cells with annexin V. Furthermore, the cellular caspase-3 protein expression was significantly raised by PIC-BZ. In addition, the wound healing experiment confirmed the results. To conclude, compared to pure PIC, PIC-BZ demonstrated a higher cell death-inducing activity against A549 cells.

Badr-Eldin, S. M., H. M. Aldawsari, S. Kotta, and N. A. Alhakamy, "Self-Assembled Supramolecular Hydrogel Based on α-Cyclodextrin/Poloxamer Polypseudorotaxanes for Ocular Delivery of Ciprofloxacin", International Journal of Pharmacology, vol. 17, issue 1, pp. 15-27, 2021.
Koshak, A. E., M. M. Algandaby, M. I. Mujallid, A. B. Abdel-Naim, N. A. Alhakamy, U. A. Fahmy, A. Alfarsi, S. M. Badr-Eldin, T. Neamatallah, M. Z. Nasrullah, et al., "Wound Healing Activity of Fixed Oil Formulated in a Self-Nanoemulsifying Formulation.", International journal of nanomedicine, vol. 16, pp. 3889-3905, 2021. Abstract

INTRODUCTION: Delayed wound healing represents a common health hazard. Traditional herbal products have been often utilized to promote wound contraction. The current study aimed at assessing the wound healing activity of seed oil (OFI) and its self-nanoemulsifying drug delivery system (OFI-SNEDDS) formula in a rat model of full-thickness skin excision.

METHODS: Based on droplet size, an optimized OFI-SNEDDS formula was prepared and used for subsequent evaluation. Wound healing activity of OFI and OFI-SNEDDS was studied in vivo.

RESULTS: The optimized OFI-SNEDDS formula droplet size was 50.02 nm. The formula exhibited superior healing activities as compared to regular OFI seed oil-treated rats at day 14 of wounding. This effect was further confirmed by histopathological examinations of H&E and Masson's Trichrome-stained skin sections. Moreover, OFI-SNEDDS showed the highest antioxidant and anti-inflammatory activities as compared to OFI seed oil-treated animals. Both OFI and OFI-SNEDDS significantly enhanced hydroxyproline skin content and upregulated Col1A1 mRNA expression, accompanied by enhanced expression of transforming factor-beta (TGF-β). Further, OFI-SNEDDS improved angiogenesis as evidenced by increased expression of vascular endothelial growth factor (VEGF).

CONCLUSION: OFI possesses wound healing properties that are enhanced by self-emulsification of the oil into nano-droplets. The observed activity can be attributed, at least partly, to its anti-inflammatory, pro-collagen and angiogenic properties.

2020
Ahmed, O. A. A., U. A. Fahmy, S. M. Badr-Eldin, H. M. Aldawsari, Z. A. Awan, H. Z. Asfour, A. K. Kammoun, G. Caruso, F. Caraci, A. Alfarsi, et al., "Application of Nanopharmaceutics for Flibanserin Brain Delivery Augmentation Via the Nasal Route.", Nanomaterials (Basel, Switzerland), vol. 10, issue 7, 2020. Abstract

Flibanserin (FLB) is a nonhormonal medicine approved by the Food and Drug Administration (FDA) to treat the hypoactive sexual appetite disorder in females. However, the peroral administration of the medicine is greatly affected by its poor bioavailability as a result of its extensive first-pass effect and poor solubility. Aiming at circumventing these drawbacks, this work involves the formulation of optimized FLB transfersome (TRF) loaded intranasal hydrogel. Box-Behnken design was utilized for the improvement of FLB TRFs with decreased size. The FLB-to-phospholipid molar ratio, the edge activator hydrophilic lipophilic balance, and the pH of the hydration medium all exhibited significant effects on the TRF size. The optimized/developed TRFs were unilamellar in shape. Hydroxypropyl methyl cellulose based hydrogel filled with the optimized FLB TRFs exhibited an improved ex vivo permeation when compared with the control FLB-loaded hydrogel. In addition, the optimized TRF-loaded hydrogel exhibited higher bioavailability and enhanced brain delivery relative to the control hydrogel following intranasal administration in Wistar rats. The results foreshadow the possible potential application of the proposed intranasal optimized FLB-TRF-loaded hydrogel to increase the bioavailability and nose-to-brain delivery of the drug.

Ahmed, O. A. A., and S. M. Badr-Eldin, "Biodegradable self-assembled nanoparticles of PEG-PLGA amphiphilic diblock copolymer as a promising stealth system for augmented vinpocetine brain delivery.", International journal of pharmaceutics, vol. 588, pp. 119778, 2020. Abstract

Vinpocetine (VNP), a semisynthetic drug, is utilized for the treatment of cerebrovascular and memory disorders. This work aimed at formulation of biodegradable VNP long-circulating nanoparticles utilizing Polyethylene glycol methyl ether-block-poly lactide-co-glycolide (PEG-PLGA) copolymer to surmount the drug drawbacks including low oral bioavailability and short elimination half-life. VNP nanoparticles were formulated using nanoprecipitation technique. A 2 factorial design was applied to assess the impact of formulation and process variables on the nanoparticles' characteristics. Statistical analysis revealed that nanoparticles size (Y) significantly increased with increasing PEG-PLGA amount (X), poly-vinyl alcohol concentration (X), and PLGA content (X), while decreased with increasing sonication time (X). Furthermore, the entrapment efficiency (Y) was positively affected by both PEG-PLGA amount and PLGA content, while negatively affected by poly-vinyl alcohol concentration. The optimized formulation prepared using 200 mg of PEG-PLGA polymer (PEG: PLGA 2000: 4,500), 0.5% polyvinyl alcohol with sonication time of 60 s achieved spherical shape with particle size of 43 nm and drug entrapment of 82%. A significant bioavailability enhancement of VNP with marked prolongation of the in vivo systemic exposure of the drug and increased brain levels has also been achieved following intraperitoneal administration in Wistar rats. Thus, the optimized formulation could be regarded as a promising stealth nanocarrier that could surmount the drug pitfalls and enhance its brain delivery.

Kotta, S., H. M. Aldawsari, S. M. Badr-Eldin, N. A. Alhakamy, S. Md, A. B. Nair, and P. K. Deb, "Combating the Pandemic COVID-19: Clinical Trials, Therapies and Perspectives.", Frontiers in molecular biosciences, vol. 7, pp. 606393, 2020. Abstract

The coronavirus disease-19 (COVID-19) is caused due to the infection by a unique single stranded enveloped RNA virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The COVID-19 has claimed many lives around the globe, and a promising solution to end this pandemic is still awaited. Till date neither an exact antiviral drug nor a vaccine is available in the market for public use to cure or control this pandemic. Repurposed drugs and supportive measures are the only available treatment options. This systematic review focuses on different treatment strategies based on various clinical studies. The review discusses all the current treatment plans and probable future strategies obtained as a result of a systematic search in PubMed and Science Direct database. All the possible options for the treatment as well as prophylaxis of COVID-19 are discussed. Apart from this, the article provides details on the clinical trials related to COVID-19, which are registered under ClinicalTrials.gov. Potential of drugs based on the previous researches on SARS-CoV, MERS-CoV, Ebola, influenza, etc. which fall under the same category of coronavirus are also emphasized. Information on cell-based and immunology-based approaches is also provided. In addition, miscellaneous therapeutic approaches and adjunctive therapies are discussed. The drug repurposing options, as evidenced from various and models, are also covered including the possible future solutions to this pandemic.

Badr-Eldin, S. M., N. A. Alhakamy, U. A. Fahmy, O. A. A. Ahmed, H. Z. Asfour, A. A. Althagafi, H. M. Aldawsari, W. Y. Rizg, W. A. Mahdi, A. F. Alghaith, et al., "Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates.", Frontiers in pharmacology, vol. 11, pp. 642171, 2020. Abstract

Fluvastatin (FLV) is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor often used to lower total and low-density lipoprotein (LDL) cholesterol and for the prevention of adverse cardiovascular events. This drug as well as melittin (MEL), the major component of honeybee venom (), has shown antineoplastic activity, then representing promising approaches for cancer therapy. However, adverse effects related to the use of FLV and MEL have been reported and very few studies have been carried out to obtain an optimized formulation allowing for combining the two drugs and then maximizing the anticancer activity, then minimizing the needed dosage. In the present study, an optimized formulation in terms of minimized particle size and maximized zeta potential was investigated for its cytotoxic potential in human OVCAR3 ovarian cancer cells. FLV-MEL nano-conjugates, containing a sub-toxic concentration of drug, demonstrated an improved cytotoxic potential (IC50 = 2.5 µM), about 18-fold lower, compared to the free drug (IC50 = 45.7 µM). Cell cycle analysis studies demonstrated the significant inhibition of the OVCAR3 cells proliferation exerted by FLV-MEL nano-conjugates compared to all the other treatments, with a higher percentage of cells accumulating on G2/M and pre-G1 phases, paralleled by lower percentage of cells in G0/G1 and S phases. The synergistic antineoplastic activity of FLV and MEL combined in the optimized formula was also showed by the marked pronecrotic and pro-apoptotic activities, the latter mediated by the modulation of BAX/BCL-2 ratio in favor of BAX. Our optimized FLV-MEL formulation might therefore represents a novel path for the development of specific and more effective antineoplastic drugs directed against ovarian cancer.

Fahmy, U. A., H. M. Aldawsari, S. M. Badr-Eldin, O. A. A. Ahmed, N. A. Alhakamy, H. H. Alsulimani, F. Caraci, and G. Caruso, "The Encapsulation of Febuxostat into Emulsomes Strongly Enhances the Cytotoxic Potential of the Drug on HCT 116 Colon Cancer Cells.", Pharmaceutics, vol. 12, issue 10, 2020. Abstract

Febuxostat (FBX) is a drug able to inhibit xanthine oxidase and reduce uric acid production commonly used for the treatment of hyperuricemia in subjects suffering from gout. Several studies have also been directed at its use as anti-cancer drug during the last years, opening a window for its off-label use. In the present study, an optimized formulation in terms of vesicle size and drug release, obtained by encapsulation of FBX into the emulsomes (FBX-EMLs), was evaluated for its cytotoxic potential in human colorectal carcinoma (HCT 116) cells. The optimized FBX-EMLs formula had an improved half maximal inhibitory concentration (IC50), about 4-fold lower, compared to the free drug. The cell cycle analysis showed a significant inhibition of the HCT 116 cells proliferation following FBX-EMLs treatment compared to all the other conditions, with a higher number of cells accumulating on G2/M and pre-G1 phases, paralleled by a significant reduction of cells in G0/G1 and S phases. The optimized formula was also able to significantly increase the percentage of cell population in both early and late stages of apoptosis, characterized by a higher intracellular caspase-3 concentration, as well as percentage of necrotic cells. Lastly, the FBX ability to decrease the mitochondrial membrane potential was enhanced when the drug was delivered into the EMLs. In conclusion, the new formulation of FBX into EMLs improved all the parameters related to the anti-proliferative activity and the toxic potential of the drug towards colorectal cancer cells.

Awan, Z. A., U. A. Fahmy, S. M. Badr-Eldin, T. S. Ibrahim, H. Z. Asfour, M. W. Al-Rabia, A. Alfarsi, N. A. Alhakamy, W. H. Abdulaal, H. Al Sadoun, et al., "The Enhanced Cytotoxic and Pro-Apoptotic Effects of Optimized Simvastatin-Loaded Emulsomes on MCF-7 Breast Cancer Cells.", Pharmaceutics, vol. 12, issue 7, 2020. Abstract

Statins, including simvastatin (SMV), are commonly used for the control of hyperlipidaemia and have also proven therapeutic and preventative effects in cardiovascular diseases. Besides that, there is an emerging interest in their use as antineoplastic drugs as demonstrated by different studies showing their cytotoxic activity against different cancer cells. In this study, SMV-loaded emulsomes (SMV-EMLs) were formulated and evaluated for their cytotoxic activity in MCF-7 breast cancer cells. The emulsomes were prepared using a modified thin-film hydration technique. A Box-Behnken model was used to investigate the impact of formulation conditions on vesicle size and drug entrapment. The optimized formulation showed a spherical shape with a vesicle size of 112.42 ± 2.1 nm and an entrapment efficiency of 94.34 ± 1.11%. Assessment of cytotoxic activities indicated that the optimized SMV-EMLs formula exhibited significantly lower half maximal inhibitory concentration (IC50) against MCF-7 cells. Cell cycle analysis indicated the accumulation of cells in the G2-M phase as well as increased cell fraction in the pre-G1 phase, suggesting an enhancement of anti-apoptotic activity of SMV. The staining of cells with Annex V revealed an increase in early and late apoptosis, in line with the increased cellular content of caspase-3 and Bax. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. In conclusion, SMV-EMLs demonstrated superior cell death-inducing activity against MCF-7 cells compared to pure SMV. This is mediated, at least in part, by enhanced pro-apoptotic activity and MMP modulation of SMV.

Aldawsari, H. M., and S. M. Badr-Eldin, "Enhanced pharmacokinetic performance of dapoxetine hydrochloride via the formulation of instantly-dissolving buccal films with acidic pH modifier and hydrophilic cyclodextrin: Factorial analysis, and assessment.", Journal of advanced research, vol. 24, pp. 281-290, 2020. Abstract

Instantly dissolving buccal films have gained attention owing to their easy administration and capability to surmount the hepatic first pass effect of drugs. Dapoxetine hydrochloride (DPX) has a low oral bioavailability due to significant hepatic first pass metabolism. In addition, DPX is a weakly basic drug with a pH dependent solubility that could limit its dissolution in the body neutral fluids. In order to surpass these challenges, this work aimed at enhancing DPX bioavailability via the formulation of instantly dissolving buccal films comprising a pH modifier and a hydrophilic cyclodextrin. Tartaric acid and hydroxypropyl beta-cyclodextrin were selected as dual solubilizing agents based on the screening study. 3 factorial design was employed for the formulation and optimization of DPX films. Statistical analysis revealed that hydroxypropyl methyl cellulose E5: maltodextrin ratio and propylene glycol concentrations have significant effects on mechanical properties, percent DPX dissolved after 5 min, and mouth dissolving time at  < 0.05. The optimized film [HPMC E5: MDX, 1:1 and 1% PG] showed no significant change of properties or drug dissolution upon storage at 40 °C/75% RH for a period of 3 months. In addition, the optimized film showed significantly enhanced absorption relative to the oral reference tablet. Therefore, the optimized film could be considered a promising delivery system for DPX with expected improved patient compliance and enhanced pharmacokinetic performance.

Kotta, S., H. M. Aldawsari, S. M. Badr-Eldin, N. A. Alhakamy, S. Md, A. B. Nair, and P. K. Deb, "Exploring the Potential of Carbon Dots to Combat COVID-19.", Frontiers in molecular biosciences, vol. 7, pp. 616575, 2020. Abstract

Viral diseases are considered as a global burden. The eradication of viral diseases is always a challenging task in medical research due to the high infectivity and mutation capability of the virus. The ongoing COVID-19 pandemic is still not under control even after several months of the first reported case and global spread. Neither a specific drug nor a vaccine is available for public use yet. In the pursuit of a promising strategy, carbon dots could be considered as potential nanostructure against this viral pandemic. This review explores the possibility of carbon nano-dots to combat COVID-19 based on some reported studies. Carbon dots are photoluminescent carbon nanoparticles, smaller than 10 nm in dimension with a very attractive photostable and biocompatible properties which can be surfaced modified or functionalized. These photoluminescent tiny particles have captured much attention owing to their functionalization property and biocompatibility. In response to this pandemic outbreak, this review attempts to summarize the potential use of carbon dots in antiviral therapy with particular emphasis on their probable role in the battlefront against COVID-19 including their possible biosensing applications.

Fahmy, U. A., S. M. Badr-Eldin, O. A. A. Ahmed, H. M. Aldawsari, S. Tima, H. Z. Asfour, M. W. Al-Rabia, A. A. Negm, M. H. Sultan, O. A. A. Madkhali, et al., "Intranasal Niosomal Gel as a Promising Approach for Enhancing Flibanserin Bioavailability and Brain Delivery: In Vitro Optimization and / Evaluation.", Pharmaceutics, vol. 12, issue 6, 2020. Abstract

Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box-Behnken design was employed to study the impact of Span 85 concentration (X), hydration time (X), and pH of the hydrating buffer (X) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain.

Naguib, M. J., S. Salah, S. A. Abdel Halim, and S. M. Badr-Eldin, "Investigating the potential of utilizing glycerosomes as a novel vesicular platform for enhancing intranasal delivery of lacidipine.", International journal of pharmaceutics, vol. 582, pp. 119302, 2020. Abstract

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

Alhakamy, N. A., S. M. Badr-Eldin, O. A. A. Ahmed, A. A. Halwani, H. M. Aldawsari, M. A El-Moselhy, A. Anter, S. S. Sharkawi, M. H. Sultan, O. A. A. Madkhali, et al., "Optimized Ellagic Acid-Ca Pectinate Floating Beads for Gastroprotection against Indomethacin-Induced Gastric Injury in Rats.", Biomolecules, vol. 10, issue 7, 2020. Abstract

A peptic ulcer is an alimentary tract injury that leads to a mucosal defect reaching the submucosa. This work aimed to optimize and maximize ellagic acid (EA) loading in Ca pectinate floating beads to maximize the release for 24 h. Three factors were selected: Ca pectinate concentration (X1, 1-3 w/v %), EA concentration (X2, 1-3 w/v %) and the dropping time (X3, 10-30 min). The factorial design proposed eight formulations. The optimized EA-Ca pectinate formulation was evaluated for the gastric ulcer index and the oxidative stress parameter determination of gastric mucosa. The results indicated that the optimum EA-Ca pectinate formula significantly improved the gastric ulcer index in comparison with raw EA. The protective effect of the optimized EA-Ca pectinate formula was further indicated by the histopathological features of the stomach. The results of the study indicate that an EA formulation in the form of Ca pectinate beads would be effective for protection against gastric ulcers because of Nonsteroidal anti-inflammatory drugs (NSAID) administration.