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.

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.

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.

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.

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.

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.

Alhakamy, N. A., S. M. Badr-Eldin, U. A. Fahmy, N. K Alruwaili, Z. A. Awan, G. Caruso, M. A. Alfaleh, A. L. Alaofi, F. O. Arif, O. A. A. Ahmed, et al., "Thymoquinone-Loaded Soy-Phospholipid-Based Phytosomes Exhibit Anticancer Potential against Human Lung Cancer Cells.", Pharmaceutics, vol. 12, issue 8, 2020. Abstract

Thymoquinone (TQ), a natural polyphenol, has been associated with various pharmacological responses; however, low bioavailability of TQ limits its clinical application. Thus, a novel phytosomal delivery system of TQ-Phospholipon 90H complex (TQ-phytosome) was developed by refluxing combined with anti-solvent precipitation. This TQ delivery system was optimized by a three-factor, three-level Box-Behnken design. The optimized TQ-phytosome size was (45.59 ± 1.82 nm) and the vesicle size was confirmed by transmission electron microscopy. The in vitro release pattern of the formulation indicated a biphasic release pattern, where an initial burst release was observed within 2 h, followed by a prolonged release. A remarkable increase in dose-dependent cytotoxicity was evident from the significant decrease in IC value of TQ-phytosomes (4.31 ± 2.21 µM) against the A549 cell line. The differential effect of TQ-phytosomes in cell cycle analysis was observed, where cancer cells were accumulated on G2-M and pre-G1 phases. Furthermore, increased apoptotic induction and cell necrosis of TQ-phytosomes were revealed with the annexin V staining technique via activation of caspase-3. In reactive oxygen species (ROS) analysis, TQ-phytosomes acted to significantly increase ROS generation in A549 cells. In conclusion, the sustained release profile with significantly-improved anticancer potential could be obtained with TQ by this phytosomal nanocarrier platform.

Fahmy, U. A., O. A. A. Ahmed, S. M. Badr-Eldin, H. M. Aldawsari, S. Z. Okbazghi, Z. A. Awan, M. A. Bakhrebah, M. N. Alomary, W. H. Abdulaal, C. Medina, et al., "Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin.", International journal of nanomedicine, vol. 15, pp. 5253-5264, 2020. Abstract

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery.

Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, ), liquid lipid % (LL%, ), and sonication time (ST, ) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats.

Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs.

Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.

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.

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.

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