This review summarizes current knowledge about the occurrence of hearing and balance disorders after antimalarial drugs treatment. It also examines the clinical applications of antimalarials, their mechanisms behind this ototoxicity and how it can be monitored. It includes studies with larger numbers of patients and those in which auditory function was assessed using audiological tests. Some antimalarials have been repurposed for other conditions like autoimmune disorders, rheumatic diseases, some viral diseases and cancers. While old antimalarial drugs, such as quinoline derivatives, are known to demonstrate ototoxicity, a number of new synthetic antimalarial agents particularly artemisinin derivatives, demonstrate unknown ototoxicity. Adverse audiovestibular effects vary depending on the medication itself, its dose and route of administration, as well as the drug combination, treated disease and individual predispositions of the patient. Dizziness was commonly reported, while vestibular symptoms, hearing loss and tinnitus were observed much less frequently, and most of these symptoms were reversible. As early identification of ototoxic hearing loss is critical to introducing possible alternative treatments with less ototoxic medications, therefore monitoring systems of those drugs ototoxic side effects are much needed.

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The Ototoxicity of Antimalarial Drugs-A State of the Art Review.

Species from the genus Globularia L. have been used as healing agents for various ailments, with utilization of Globularia alypum L. being most frequently reported. The aim of this study was to evaluate the antidiabetic, antioxidant, anti-inflammatory, antibacterial and anticancer potential of G. alypum and three related species, G. punctata Lapeyr., G. cordifolia L. and G. meridionalis (Podp.) O.Schwarz, in relation to their phytochemical compositions. Globularin and verbascoside were identified using LC-PDA-ESI-MSn as the major metabolites of G. alypum with known biological activities. G. alypum demonstrated the greatest α-glucosidase inhibitory activity and DPPH radical scavenging activity (IC50 = 17.25 μg/mL), while its anti-inflammatory activity was not significantly different from those of related species. All investigated species showed considerable antibacterial activity against methicillin-resistant Staphylococcus aureus in the broth microdilution method (MIC = 1.42–3.79 mg/mL). G. punctata also showed antibacterial activities against Escherichia coli (MIC = 1.42 mg/mL), Bacillus subtilis (MIC = 1.89 mg/mL), B. cereus (MIC = 2.84 mg/mL) and Enterococcus faecalis (MBC = 5.68 mg/mL). G. punctata, G. cordifolia and G. meridionalis showed greater anticancer potential than G. alypum. Obtained results indicate investigated Globularia species could serve as sources of diverse bioactive molecules, with G. punctata having the greatest antibacterial potential.

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Globularia alypum L. and Related Species: LC-MS Profiles and Antidiabetic, Antioxidant, Anti-Inflammatory, Antibacterial and Anticancer Potential

The current strategy of searching for an effective treatment for COVID-19 relies mainly on repurposing existing therapies developed to target other diseases. Conflicting results have emerged in regard to the efficacy of several tested compounds but later results were negative. The number of conducted and ongoing trials and the urgent need for a treatment pose the risk that false-positive results will be incorrectly interpreted as evidence for treatments' efficacy and a ground for drug approval. Our purpose is twofold. First, we show that the number of drug-repurposing trials can explain the false-positive results. Second, we assess the evidence for treatments' efficacy from the perspective of evidential pluralism and argue that considering mechanistic evidence is particularly needed in cases when the evidence from clinical trials is conflicting or of low quality. Our analysis is an application of the program of Evidence Based Medicine Plus (EBM+) to the drug repurposing trials for COVID. Our study shows that if decision-makers applied EBM+, authorizing the use of ineffective treatments would be less likely. We analyze the example of trials assessing the efficacy of hydroxychloroquine as a treatment for COVID-19 and mechanistic evidence in favor of and against its therapeutic power to draw a lesson for decision-makers and drug agencies on how excessive hypothesis testing can lead to spurious findings and how studying negative mechanistic evidence can be helpful in discriminating genuine from spurious results. 

/pdf/the-failure-of-drug-repurposing-for-covid-19-as-an-effect-of-116bz1j6.pdf

The failure of drug repurposing for COVID-19 as an effect of excessive hypothesis testing and weak mechanistic evidence

Background Ovarian cancer (OC) is the leading cause of gynecological cancer-related mortality. Verbascoside (VB) is a phenylpropanoid glycoside from Chinese herbs, with anti-tumour activities. This study aimed to investigate the effects and mechanism of VB on OC. Methods OC cell lines SKOV3 and A2780 were used in this study. Cell viability, proliferation, and migration were measured using CCK-8, clonogenic, and transwell assays, respectively. Apoptosis and M1/M2 macrophages were detected using flow cytometry. The interaction between VB and CCN1 was predicted by molecular docking. The mRNA expression of CCN1 was detected by RT-qPCR. The protein levels of CCN1, AKT, p-AKT, p65, and p-p65 were determined by western blotting. A xenograft mice model was established for in vivo validation. Results VB inhibited OC cell proliferation and migration in a dose-dependent manner, and promoted apoptosis and M1 macrophage polarization. VB downregulated CCN1 and inhibited the AKT/NF-κB pathway. LY294002, an AKT inhibitor, potentiated the anti-tumour effects of VB. CCN1 overexpression weakened the anti-tumour effects of VB and VB + LY294002. In vivo experiments verified that VB inhibited tumour growth and promoted M1 polarization, which is regulated by the CCN1-mediated AKT/NF-κB pathway. Conclusion VB triggers the CCN1-AKT/NF-κB pathway-mediated M1 macrophage polarization for protecting against OC.

/pdf/the-anti-tumor-efficacy-of-verbascoside-on-ovarian-cancer-2fs1rk5e.pdf

The Anti-Tumor Efficacy of Verbascoside on Ovarian Cancer via Facilitating CCN1-AKT/NF-κB Pathway-Mediated M1 Macrophage Polarization

Benign prostatic hyperplasia (BPH) is the most common prostate disease and one of the most common chronic diseases caused by aging in men. On the other hand, there has been no research on BPH using Abeliophyllum distichum Nakai (A. distichum). Therefore, this study investigated the effects of A. distichum on BPH.A. distichum leaves were extracted with distilled water, 70% ethanol, and 95% hexane as solvents. Subsequently, the inhibitory effects of each A. distichum extract on androgen receptor (AR) signaling were evaluated in vitro. The testosterone-induced BPH model was then used to confirm the efficacy of A. distichum leaves in 70% ethanol extract (ADLE).ADLE had the strongest inhibitory effect on AR signaling. A comparison of the activity of ADLE by harvest time showed that the leaves of A. distichum harvested in autumn had a superior inhibitory effect on AR signaling to those harvested at other times. In the BPH rat model, the administration of ADLE reduced the prostate size and prostate epithelial cell thickness significantly and inhibited AR signaling. Subsequently, the administration of ADLE also reduced the expression of growth factors, thereby inactivating the PI3K/AKT pathway.An analysis of the efficacy of ADLE to relieve BPH showed that the ethanol extract grown in autumn exhibited the highest inhibitory ability of the androgen-signaling related factors in vitro. ADLE also inhibited the expression of growth factors by inhibiting the expression of the androgen-signaling related factors in vivo. Overall, ADLE is proposed as a functional food that is effective in preventing BPH. 

Ameliorative effect of Abeliophyllum distichum Nakai on benign prostatic hyperplasia in vitro and in vivo

Cancer is a set of diseases including abnormal growth of cells that can spread to another tissue. Verbascoside (or acteoside) is a naturally occurring, water-soluble secondary metabolite with significant biological properties, which is distributed widely in plant kingdom. Verbascoside is pharmacologically active compounds with many recent evidences that support its biological activities and safety. This review focuses on the recent studies that concerned with the antitumor activities of verbascoside alone and as a synergistic agent as well as nanoproduct. It also shows the latest advances in its antitumor effects, cytotoxic selectivity and its efficiencies in treating cancer, in vitro and/or vivo.

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Verbascoside—A Review of Its Antitumor Activities

Chloroquine (CQ) was and still considered as the most
common agent in the treatment and prophylaxis of malaria, it also possesses many different
pharmacological and biological activities that make it able to be used as a
therapy or adjuvant therapy for many types of diseases. CQ exhibits anticancer
activity alone or as adjuvants with other agents against many kinds of tumors.
Its activities also were approved as an anti-inflammatory agent in rheumatoid and other autoimmune diseases like
systemic lupus and rheumatic arthritis. Its’ important role in the improvement of many metabolic disorders like
hypertension, hyperglycemia, and lipid profile disturbances was also
established. CQ can act against different microbial infections such as many
types of viruses, bacteria and fungus by different mechanisms of action. Furthermore, its
dermatological role in the treatment of many skin diseases was demonstrated. Recently, CQ showed a very
responsive role in curing and prevention of the covoid-19 virus. This review summarizes intensively the multiple
therapeutic applications of CQ and discusses the possible mechanisms of action
for these applications.

/pdf/wide-applications-of-chloroquine-other-than-antimalarial-1zho2efw0l.pdf

Ismail Taha Ibrahim

Papers

Verbascoside—A Review of Its Antitumor Activities

Wide Applications of Chloroquine Other Than Antimalarial