Current Drug Therapy - Volume 16, Issue 4, 2021

The COVID-19 pandemic has caused serious concerns for people around the world. The COVID-19 is associated with respiratory failure, generation of reactive oxygen species (ROS), and the lack of antioxidants among patients. Specified ROS levels have an essential role as an adjuster of immunological responses and virus cleaners, but excessive ROS will oxidize membrane lipids and cellular proteins and quickly destroy virus-infected cells. It can also adversely damage normal cells in the lungs and even the heart, resulting in multiple organ failures. Given the above, a highly potent antioxidant therapy can be offered to reduce cardiac loss due to COVID-19. In modern medicine, nanoparticles containing antioxidants can be used as a high-performance therapy in reducing oxidative stress in the prevention and treatment of infectious diseases. This can provide a free and interactive tool to determine whether antioxidants and nanoantioxidants can be administered for COVID-19. More research and studies are needed to investigate and make definitive opinions about their medicinal uses.

Despite the endeavors and maneuvers in cancer treatment, drug resistance and toxicities have become a significant obstacle these days. Diverseness among the patients and tumor and the multifaceted nature of cancer to circumvent therapies make it more challenging. Adenosine monophosphate-activated protein kinase (AMPK) is a significant biosensor and it negatively regulates cancer growth by inhibiting the mechanistic target of rapamycin (mTOR) signaling cascade, which is responsible for cell growth and proliferation. These two critical regulators of growth are often found deregulated in human cancers. They act by triggering the AMPK pathway, thereby inducing mTOR inhibition leading to dephosphorylation of its downstream regulators S6K1 and 4EBP1, with two key regulators TSC2 and RHEB. Drugs like biguanides, Aspirin, resveratrol, quercetin, and some natural products were found to decrease cancer incidence by this cognate pathway. This pathway drew more attention for better strategies to enhance the treatment efficacy, but adequate evidence in this field is still lacking. Repurposing existing drugs with multimodal actions and fewer toxicities could be considered for newer therapies. Combined effects of an AMPK activator drug with an mTOR inhibitor when used in conjunction or a new drug developed with the above dual properties could be a promising strategy in this sector. Thus, scouting the significance of this pathway and combination therapies in a more personalized manner would be indeed a turning point for future investigations.

Background: Valerian root extract is used in traditional medicine to treat sleep disorders. According to previous studies, sedative effects are related to the presence of valerenic acid. Formulating orodispersible tablets (ODTs) is an effective and cost-benefit technique for accelerating drugs' therapeutic effects. This study aimed to formulate ODTs of valerian root extract and evaluate their properties. Materials and Methods: Valerian root was extracted by percolation in 70% ethanol. The solubility of valerenic acid was investigated in various liquid carriers. The extract was uniformly dispersed in the selected carrier (Tween 80), then mixed with other excipients, and compressed into tablets. Fourteen formulations with different amounts of sodium starch glycolate (SSG, as a super disintegrant) and camphor (as a sublimating agent) were prepared. The physicochemical properties of the ODTs, drug release rates, and microbial limit tests (MLTs) were studied. Results: Both SSG and camphor accelerated tablet disintegration rates and their composition showed a synergistic effect (P<0.05). The infrared spectroscopy revealed no chemical interaction between formulation components. The MLTs confirmed that a limited number of microbial colonies were grown in the liquid medium, and no pathogen growth occurred in the specific culture media. Conclusion: The results revealed that Valerian ODT's physicochemical properties were significantly improved compared to conventional tablets. The technique can be utilized for other poorly watersoluble pharmaceuticals.

Background: The present research aimed to develop and optimize extended-release floating tablets of Sacubitril and Valsartan by Quality by Design (QbD) approach. Methods: Risk analysis by formulation assessment and process parameters showed that optimizing the levels of the polymer will minimize the high risk to meet the target profile. A two (2) level three (3) full factorial experimental design along with midpoints was carefully chosen for optimization and statistical analysis. Based on the literature, the independent and dependent variables were selected. Results: HPMC K100, Carbopol 934P had a positive effect, Ethyl cellulose with the negative effect on Floating time, Drug release at 2 h, Drug release at 12 h and, t50% responses. Drug release kinetics followed the first-order release with Higuchi and fickian diffusion. Contour and overlay plots were utilized for an assortment of design space and optimized formula. ANOVA results of all the factors exhibited significance at p < 0.05. Abdominal X-ray imaging of the optimized tablets on a healthy rabbit’s stomach confirmed the floating behavior for more than 12 h. In vivo pharmacokinetic studies in rabbits have shown that the optimized formulation exhibited prolonged and extended drug release with improved Cmax, tmax, AUCo-t, and t1/2 of test product when compared to marketed product. IVIVC model was developed by using dissolution data of in vitro and pharmacokinetics data of in-vivo by deconvolution method (Wagner-Nelson method). Conclusion: The Quality by Design implementation in the formulation and optimization abridged the number of trials to produce a cost-effective formula. In vivo studies have demonstrated that the formula was successfully developed with extended floating time (12 h) and drug release by risk analysis and experimental designs. Level A correlation was observed, which confirmed a good correlation between in vitro and in vivo data.

Background: Over the years, effervescent orally disintegrating tablets (ODTs) have proved their worth over conventional tablets in overcoming the swallowing problems associated with the geriatric and pediatric population. The addition of effervescent agents in ODT provides a rapid disintegration along with masking of the slight bitter taste of drugs and is worth exploring. Objective: The present research investigation deals with the preparation of effervescent ODTs by direct compression with rapid disintegration and adequate hardness using the central composite design response surface methodology. Methods: Central composite design was used to study the effect of concentration of crospovidone (X1) and concentration of citric acid and sodium bicarbonate (X2) as independent factors on the two responses: disintegration time (Y1) and drug release (Y2). The tablets were prepared by direct compression approach using directly compressible mannitol. Results: The optimization results obtained after application of ANOVA revealed that increase in the concentration of X1 and X2 resulted in the increase in disintegration time and % CDR. Following the statistical analysis of the results, the formulation batch (F-7) with a desirability index of 0.95 was chosen as optimized batch and exhibited 99±0.8 % release of the drug after 5 min, and rapid disintegrating time of 31±3 sec. All other tablet attributes were well within the official limits. Conclusion: The results obtained in the present investigation clearly revealed a successful development of famotidine effervescent ODTs with a better release profile in comparison to marketed formulation.

Background: Gout is a metabolic disease strictly related to hyperuricemia. The associated intense inflammation and pain are triggered by the deposited monosodium urate crystals (MSU) in joints. The principal therapeutic strategies of gout involve the control of hyperuricemia and antiinflammatory medications. Objectives: This study aimed to investigate the possible beneficial effects of ozone therapy, a wellknown antioxidant and an immunomodulator, on gouty arthritis and the underlying mechanisms. Methods: Acute gouty arthritis was induced in male albino rats via MSU crystals intra-articular injection in the ankle joint. The gouty arthritic rats received pre-treatment with ozone, colchicine (as a reference drug), or their combination. Results: The obtained results of ozone therapy showed an obvious reduction in the degree of edematous ankle swelling, pro-inflammatory cytokines, lipid peroxidation, the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3), procaspase-1, caspase-1, interleukin- 1β synovial tissue levels with an enhancement of antioxidant defense system. Additionally, ozone therapy significantly attenuated the histological derangements in gouty arthritic rats. Conclusion: This study suggests that ozone is able to treat gouty arthritis and reducing synovial injury through an anti-inflammatory effect as well as antioxidant activity.

Background: Acute myeloid leukemia (AML) is an aggressive type of leukemia adversely affecting the normal differentiation and proliferation process of human hematopoietic myeloid lineage. Over the last decades, Kaempferol (Kae) (3,4′,5,7-tetrahydroxyflavone) has been considered a flavonoid with useful medical significance, capable of inhibiting various types of leukemia (e.g., AML). Objective: This study aimed to evaluate the Kae effect on proliferation and apoptosis of a human AML cell line, HL60. Methods: The proliferation capability of the HL60 cells was estimated by MTT assay at 12, 24, and 48 hours after exposure to Kae at a series of concentrations, including 10, 25, 50, and 75 μM. Also, the apoptosis level of HL60 cells was measured 48 hours after exposure to various concentrations of Kae (10, 25, and 50 μM) using Annexin-V/PI staining and FACS analysis. Besides, the gene expression of CDK1/2, Bcl-2, survivin, c-FLIP, Mcl-1, XIAP, Bax, and caspase 3 and 8 was assessed following treatment of HL60 cells with Kae (25 and 50 μM) by Real-Time PCR. Results: The anti-proliferation activity of Kae showed an ascending pattern over time and reached the maximum level at 48 hours of HL60 cells exposure to Kae. Also, it was able to trigger apoptosis of HL60 cells, in particular, at 50 μM concentration. On the other hand, Kae could modify the expression levels of the candidate’s genes in treated cells. Conclusion: The promising results of using Kae against the HL60 cells have made it a good drug candidate to treat AML through up-regulation of caspases expression and down-regulation of antiapoptotic proteins.

Background: The coronavirus disease 2019 (COVID-19) is a contagious disease originating from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Previous experimental studies indicated that during viral infections, viral miRNAs (vmiRNAs) played key roles in pathogen-host interaction, immune escape, host cell death, and tumorigenesis. MiRNAs are small, single-stranded RNAs that exist in viruses as well as in animals. Thus, these molecules can play a pivotal role in viral disease pathogenesis. Objective: Since no approved drugs or vaccines currently exist for SARS-CoV-2 and its pathogenic mechanism is unknown, the present study aimed to explore and propose vmiRNA platforms as potential antiviral therapeutic agents against SARS-CoV-2. The development of antiviral drugs to target vmiRNAs may result in the down-regulation of viral virulence genes expression and suppression of viral proliferation. Methods: In this study, to attain insight into the potential role of SARS-CoV-2-derived miRNAs in viral infections, a set of computational methods was used to scan the SARS-CoV-2 genome, eventually predicting 13 potential candidate vmiRNAs. Furthermore, the potential genes were predicted in the human hosts that were the target of these candidate vmiRNAs by applying the mirPath software. Results: This study proposed a theory indicating that the predicted vmiRNAs might have a plausible role in altering human target gene expression, mainly contributing to a viral infectious state, inflammation, and immune system escape. These vmiRNAs might have therapeutic trends as antiviral agents against COVID-19 infection. Conclusion: The findings offered a reference idea for a supplementary study on miRNA identification as a drug target and revealed the necessity to increase the understanding of SARS-CoV-2 genome structure for a better combat against the virus.