The ethnopharmacological study of plant drugs used traditionally in Djibouti for malaria treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Djibouti was a country where malaria has been endemic for centuries. The local population use the plants as repellents or first aid for uncomplicated malaria. AIM OF THE STUDY: The aim was, for the first time, to collect and identify plants used by the local population to treat malaria and select the most interesting plants (those that are more commontly used, more available, and have fewer studies). These plants were evaluated for their antiplasmodial activity as well as their cytotoxicity on human cell lines for the most active ones. MATERIALS AND METHODS: A semi-structured questionnaire was developed for this study to collect information about the use and identity of botanical drugs used to treat malaria. The use-reports (percentage) of each plant were recorded to determine their use importance. Also, the availability status of the plants was assessed; and those in critical condition were discarded excluded from further study. Fifteen plants, out of the 41 listed, were extracted with hydro alcohol, ethyl acetate, and dichloromethane for biological testing. Chloroquine-resistant strain FcB-1 of P. falciparum and a human diploid embryonic lung cell line were used for the antiplasmodial test, and to assess the cytotoxicity for human cells respectively. Preliminary analysis of extract constituents was carried out using thin layer chromatography (TLC). RESULTS: This study identifies 41 plant taxa belonging to 32 families and records their use against malaria. Balanites rodunfolia, belonging to the Zygophyllaceae family, was the most commonly used plant, representing 44 % of use-reports. It was followed by Cadaba rodunfolia (15 %) from the Capparaceae family, and then the three species of Aloe: Aloe djiboutiensis (8.2 %), Aloe ericahenriettae (3.4 %), and Aloe rigens (3.4 %) from the Asphodelaceae family. The leaves are the most commonly used part of the plants to treat malaria, accounting for 76 % of usage. The preparation methods were decoction (52 %), maceration (29 %), and boiling (19 %). The administration routes were by oral (80 %), inhalation 19 %), and bathing (1 %). The best antiplasmodial activities were observed in the dichloromethane extracts of Cymbopogon commutatus and the ethyl acetate extracts of Aloe rigens and Terminalia brownii, with IC50 values of 9.8, 5, and 7.5 µg/mL, respectively. Their toxicity/activity levels were very favorable with selectivity indices of 5.6, 8.1, and 11.8 for C. commutatus, A. rigens, and T. Brownii, respectively. CONCLUSION: Forty-one species of botanical drugs were listed as being used to treat malaria in Djibouti. All fifteen selected species showed antiplasmodial activity (IC50 < 50 µg/mL). This work will help guide the valorization of botanical drugs used to treat malaria in Djibouti.

PLM-101 is a novel and potent FLT3/RET inhibitor with less adverse effects in the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML.

Convex optimization for maximizing the degradation efficiency of chloroquine in a flow-by electrochemical reactor.

The degradation efficiency of chloroquine phosphate (CQ), an anti-COVID-19 drug, was investigated in a flow-by electrochemical reactor (FBER) provided with two boron-doped diamond (BDD) electrodes (as cathode and anode) under batch recirculation mode. A central composite rotatable design (CCRD) was run down to model and assess the influence of initial pH in an interval of 3.71 to 11.28, the current density in an interval of 34.32 to 185.68 mA cm-2, and liquid volumetric flow rate in an interval of 0.58 to 1.42 L min-1, and conduct the convex optimization to obtain the maximum degradation efficiency. Experimental results were modeled through a second-order polynomial equation having a determination coefficient (R2) of 0.9705 with a variance coefficient of 1.1%. Optimal operating conditions found (initial pH of 5.38, current density (j) of 34.4 mA cm-2, and liquid flow rate (Q) of 1.42 L min-1) led to a global maximum degradation efficiency, COD removal efficiency, and mineralization efficiency of 89.3, 51.6 and 53.1%, respectively, with an energy consumption of 0.041 kWh L-1 within 9 h of treatment. Additionally, a pseudo-zero-order kinetic model was demonstrated to fit the experimental data and the calculated pseudo-zero-order kinetic constant (kapp) was 13.14 mg L-1 h-1 (2.54 × 10-5 mol dm-3 h-1). Furthermore, the total operating cost was of 0.47 US$ L-1. Finally, this research could be helpful for the treatment of wastewater containing an anti-COVID-19 drug such as CQ. Supplementary Information: The online version contains supplementary material available at 10.1007/s10008-023-05452-7.

Effect of liquiritigenin on chloroquine accumulation in digestive vacuole leading to apoptosis-like death of chloroquine-resistant P. falciparum.

BACKGROUND: Malaria remains one of the major health concerns, especially in tropical countries. Although drugs such as artemisinin-based combinations are efficient for treating Plasmodium falciparum, the growing threat from multi-drug resistance has become a major challenge. Thus, there is a constant need to identify and validate new combinations to sustain current disease control strategies to overcome the challenge of drug resistance in the malaria parasites. To meet this demand, liquiritigenin (LTG) has been found to positively interact in combination with the existing clinically used drug chloroquine (CQ), which has become unfunctional due to acquired drug resistance. PURPOSE: To evaluate the best interaction between LTG and CQ against CQ- resistant strain of P. falciparum. Furthermore, the in vivo antimalarial efficacy and possible mechanism of action of the best combination was also assessed. METHODS: The in vitro anti-plasmodial potential of LTG against CQ- resistant strain K1 of P. falciparum was tested using Giemsa staining method. The behaviour of the combinations was evaluated using the fix ratio method and evaluated the interaction of LTG and CQ by calculating the fractional inhibitory concentration index (FICI). Oral toxicity study was carried out in a mice model. In vivo antimalarial efficacy of LTG alone and in combination with CQ was evaluated using a four-day suppression test in a mouse model. The effect of LTG on CQ accumulation was measured using HPLC and the rate of alkalinization of the digestive vacuole. Cytosolic Ca2+ level, mitochondrial membrane potential, caspase-like activity, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and Annexin V Apoptosis assay to assess anti-plasmodial potential. Proteomics analysis was evaluated by LC-MS/MS analysis. RESULTS: LTG possesses anti-plasmodial activity on its own and it showed to be an adjuvant of CQ. In in vitro studies, LTG showed synergy with CQ only in the ratio (CQ: LTG-1:4) against CQ-resistant strain (K1) of P. falciparum. Interestingly, in vivo studies, LTG in combination with CQ showed higher chemo-suppression and enhanced mean survival time at much lower concentrations compared to individual doses of LTG and CQ against CQ- resistant strain (N67) of Plasmodium yoelli nigeriensis. LTG was found to increase the CQ accumulation into digestive vacuole, reducing the rate of alkalinization, in turn increasing cytosolic Ca2+ level, loss of mitochondrial potential, caspase-3 activity, DNA damage and externalization of phosphatidylserine of the membrane (in vitro). These observations indicate the involvement of apoptosis-like death of P. falciparum that might be due to the accumulation of CQ. CONCLUSION: LTG showed synergy with CQ in the ratio LTG: CQ, 4:1) in vitro and was able to curtail the IC50 of CQ and LTG. Interestingly, in vivo in combination with CQ, LTG showed higher chemo-suppression as well as enhanced mean survival time at a much lower concentrations of both the partners as compared to an individual dose of CQ and LTG. Thus, synergistic drug combination offers the possibility to enhance CQ efficacy in chemotherapy.

Molecular Docking Analysis of Adhatoda vasica with Thromboxane A2 Receptor (TXA2R) (6IIU) and Antiviral Molecules for Possible Dengue Complications.

OBJECTIVE: The present study is an in silico model of platelet amplification potential of Adhatoda vasica, which can be used to treat thrombocytopenia in dengue complications. METHODS: Docking studies have proved to be an essential tool that facilitates the structural diversity of natural products to be harnessed in an organized manner. In the present study, vasicine containing natural anti-dengue potential was subjected to docking studies using Schrodinger glides software (ver.11.1). The docking study was carried out to find out the potential molecular targets for selected protein. The docking was carried out on different ligands, like vasicine, ramatroban, chloroquine, celgosivir, and standard eltrombopag downloaded from PubChem and retrieved to glide software and ligands prepared using lig prep wizard. Docking was performed using the ligand docking wizard of Glide-maestro 2018. RESULTS: The docking score of vasicine (-5.27) is nearly identical to the standard eltrombopag (-6.08), and both ligands bind with one hydrogen bond. The validation score of ramatroban is -12.39, binding with five hydrogen bonds, Celgosivir exhibited a docking score of -7.3 with three hydrogen bonds, and chloroquine displayed no hydrogen bond but had a docking score of -4.6. CONCLUSION: Vasicine was found to be the most suitable target of platelet amplification potential from Adhatoda vasica. However, the molecular docking results are preliminary, and it has been indicated that vasicine could be one of the potential ligands to treat the thrombocytopenia of dengue; experimental evaluation will be carried out in the near future.

Self-Assembled CuCo2S4 Nanoparticles for Efficient Chemo-Photothermal Therapy of Arterial Inflammation.

Cardiovascular disease caused by atherosclerosis (AS) seriously affects human health. Photothermal therapy (PTT) brings hope to the diagnosis and treatment of AS, with the development of nanotechnology. To improve treatment efficiency, self-assembled CuCo2S4 nanocrystals (NCs) were developed as a drug-delivery nanocarrier, triggered by near-infrared (NIR) light for efficient chemophotothermal therapy of arterial inflammation. The as-prepared self-assembled CuCo2S4 NCs exhibited excellent biocompatibility and a very high chloroquine (CL)-loading content. In addition, the self-assembled CuCo2S4 NCs/CL nanocomposites showed good photothermal performance, due to strong absorption in the NIR region, and the release of CL from the NCs/CL nanocomposites was driven by NIR light. When illuminated by NIR light, both PTT from the NCs and chemotherapy from the CL were simultaneously triggered, resulting in killing macrophages with a synergistic effect. Moreover, chemo-photothermal therapy with CuCo2S4 NCs/CL nanocomposites showed an effective therapeutic effect for arterial inflammation, in vivo. Our work demonstrated that chemo-photothermal therapy could be a promising strategy for the treatment of arterial inflammation against atherosclerosis.

Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles.

BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.

Study of chloroquine susceptibility potential of plants using pseudomonas aeruginosa as in vitro model.

Chloroquine (CQ) is mainly known for antimalarial activity but due to lower sensitivity, it has not been well explored in the microbial disease treatment. In the present investigation, we attempted to enhance the CQ sensitivity in Pseudomonas aeruginosa. Presence of efflux pump is well demonstrated in bacterial system which plays an important role in drug sensitivity and resistance in bacteria and also serves other functions. Taking the advantage of presence of efflux pump in Pseudomonas aeruginosa, we made an attempt to sensitize the Pseudomonas aeruginosa with various plant extracts and phytochemicals for the development of CQ sensitivity. Ten rationally selected plant extracts were screened for the development of chloroquine sensitivity in P. aeruginosa. The chloroquine susceptibility assay was demonstrated by combining CQ and verapamil (a known efflux pump inhibitor) as a standard in an in vitro assay system. Results were quite encouraging as methanolic extracts of Syzygium aromaticum, Zingiber officinale and Curcuma longa were able to enhance chloroquine sensitivity in P. aeruginosa by increasing the zone of inhibition in well-defined assay system. These plant extracts were finally analysed for the presence of various phytochemicals. The Syzygium aromaticum extract showed the presence of phytochemicals, such as quinones, phenol, triterpenoid, saponins, tannins, alkaloids and flavonoids. On the other hand, the methanolic extract of Zingiber officinale and Curcuma longa showed the presence of saponins, tannins, alkaloids and flavonoids in the extract. Towards the identification of active principle of selected plant extract for CQ sensitivity enhancement, thin-layer chromatography was performed and various phytocomponent bands were isolated. Flavonoid (R f 0.44) in Syzygium aromaticum, alkaloid (R f 0.43) in Zingiber officinale and phenol (R f 0.62) in Curcuma longa were found responsible for the enhancement of CQ susceptibility in P. aeruginosa. This interesting finding confirmed the concept that a prior course or combination of plant extracts or phytochemicals with chloroquine can be effective against P. aeruginosa. Present investigation successfully presented the proof of concept for the enhancement of chloroquine sensitivity in bacterial system by modulating an efflux pump. Concept can be explored for repurposing chloroquine for new applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03382-1.

Review Covid-19 (sars-cov-2) and medicinal plants ­ literature / Revisão Covid-19 (sars-cov-2) e plantas medicinais - literatura / Revisión Covid-19 (sars-cov-2) y plantas medicinales - bibliografía

In December 2019, a new coronavirus originating from the city of Wuhan in China started an epidemic that brought many countries into chaos and despair. SARS-CoV-2, as identified, gave rise to the severe acute respiratory syndrome called COVID-19. Its transmission happens through droplets of saliva, hand or contaminated surfaces. Since its discovery, COVID-19 has led many to death, therefore, researchers from around the world have joined efforts to develop strategies to contain the virus. In this race, drugs such as Chloroquine and Hydroxychloroquine have become possible options for showing an antiviral effect, however, studies contest their efficiency, generating uncertainties. Therefore, other alternatives have been investigated in this context, and the study of medicinal plants has been the target of research for the treatment of COVID-19 in search of bioactive natural products that can exert an antiviral action. The study aimed to analyze the published literature on COVID-19 (SARS-CoV-2) and its relationship with medicinal plants. Bibliographical survey. So far, no specific treatment against the disease has been found, only supportive, with drugs that aim to improve the individual's immune system and ensure that the virus does not replicate, for example, there are options such as chloroquine, hydroxychloroquine, remdesivir and convalescent plasma. On the other hand, studies have revealed that medicinal plants such as garlic, among others, showed efficiency in modulating proteins with a view to preventing viral replication and improving immunity against COVID-19. So far, there are no drugs that are completely safe and have been shown to have activity against the new coronavirus (SARS-CoV-2). However, medicinal plants can contribute to the development of specific therapies against SARS-CoV-2 in a safe and effective way.

Em dezembro de 2019, um novo coronavírus originário da cidade de Wuhan, na China, iniciou uma epidemia que levou muitos países ao caos e ao desespero. O SARS-CoV-2, conforme identificado, deu origem à síndrome respiratória aguda grave chamada COVID-19. Sua transmissão acontece através de gotículas de saliva, mãos ou superfícies contaminadas. Desde sua descoberta, o COVID-19 levou muitos à morte, por isso, pesquisadores de todo o mundo uniram esforços para desenvolver estratégias para conter o vírus. Nesta corrida, medicamentos como Cloroquina e Hidroxicloroquina tornaram-se opções possíveis por apresentarem efeito antiviral, porém, estudos contestam sua eficiência, gerando incertezas. Portanto, outras alternativas têm sido investigadas nesse contexto, e o estudo de plantas medicinais tem sido alvo de pesquisas para o tratamento da COVID- 19 em busca de produtos naturais bioativos que possam exercer ação antiviral. O estudo teve como objetivo analisar a literatura publicada sobre COVID-19 (SARS-CoV-2) e sua relação com plantas medicinais. Levantamento bibliográfico. Até o momento, não foi encontrado nenhum tratamento específico contra a doença, apenas de suporte, com medicamentos que visam melhorar o sistema imunológico do indivíduo e garantir que o vírus não se replique, por exemplo, há opções como cloroquina, hidroxicloroquina, remdesivir e convalescença plasma. Por outro lado, estudos revelaram que plantas medicinais como o alho, entre outras, mostraram eficiência na modulação de proteínas visando prevenir a replicação viral e melhorar a imunidade contra a COVID-19. Até o momento, não existem medicamentos completamente seguros e que tenham demonstrado atividade contra o novo coronavírus (SARS-CoV-2). No entanto, as plantas medicinais podem contribuir para o desenvolvimento de terapias específicas contra o SARS-CoV-2 de forma segura e eficaz.

En diciembre de 2019, un nuevo coronavirus originario de la ciudad de Wuhan, en China, inició una epidemia que sumió a muchos países en el caos y la desesperación. El SARS-CoV- 2, tal y como fue identificado, dio lugar al síndrome respiratorio agudo severo denominado COVID-19. Su transmisión se produce a través de gotitas de saliva, de las manos o de superficies contaminadas. Desde su descubrimiento, el COVID-19 ha llevado a muchos a la muerte, por lo que investigadores de todo el mundo han aunado esfuerzos para desarrollar estrategias de contención del virus. En esta carrera, fármacos como la Cloroquina y la Hidroxicloroquina se han convertido en posibles opciones por mostrar un efecto antiviral, sin embargo, los estudios refutan su eficacia, generando incertidumbres. Por lo tanto, otras alternativas han sido investigadas en este contexto, y el estudio de las plantas medicinales ha sido el objetivo de la investigación para el tratamiento de COVID-19 en busca de productos naturales bioactivos que puedan ejercer una acción antiviral. El estudio tuvo como objetivo analizar la literatura publicada sobre el COVID-19 (SARS-CoV-2) y su relación con las plantas medicinales. Estudio bibliográfico. Hasta el momento, no se ha encontrado un tratamiento específico contra la enfermedad, sólo de soporte, con fármacos que buscan mejorar el sistema inmunológico del individuo y asegurar que el virus no se replique, por ejemplo, existen opciones como la cloroquina, hidroxicloroquina, remdesivir y plasma convaleciente. Por otro lado, estudios han revelado que plantas medicinales como el ajo, entre otras, mostraron eficacia en la modulación de proteínas con vistas a impedir la replicación viral y mejorar la inmunidad contra el COVID-19. Hasta el momento, no existen medicamentos que sean completamente seguros y que hayan demostrado tener actividad contra el nuevo coronavirus (SARS-CoV-2). Sin embargo, las plantas medicinales pueden contribuir al desarrollo de terapias específicas contra el SARS-CoV-2 de forma segura y eficaz.

Efficacy of glucocorticoids, chloroquine and vitamin A on cytokine release syndrome: a network pharmacology study.

OBJECTIVE: To verify the efficacy of glucocorticoids, chloroquine and vitamin A in the treatment of cytokine release syndrome (CRS), and to investigate the underlying mechanisms, based on network pharmacology. METHODS: We used network pharmacology analysis and found 20 co-targeted genes of glucocorticoids, chloroquine, vitamin A and CRS. The pharmacological functions and therapeutic pathways of the genes were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. The candidate naturally bioactive compounds against the key genes were predicted by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The anti-inflammatory activity of luteolin was assessed by real-time polymerase chain reaction. RESULTS: Among the 20 co-targeted genes of glucocorticoids, chloroquine and vitamin A, interleukin 10 (IL-10), interleukin 2 (IL-2), interleukin 4 (IL-4) and tumor necrosis factor-α (TNF-α) were the key cytokines against CRS. The key pathway involved in the pharmacological mechanism could be cytokine-cytokine receptor interaction pathway, T cell receptor signaling pathway, Janus Kinase-signal transducer and activator of transcription signaling pathway and phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Luteolin targeted by IL-10, IL-4, IL-2 and TNF-α could be one candidate drug for the treatment of CRS. CONCLUSION: This study comprehensively elucidates the pharmacological mechanism for the treatment of CRS and provides a new method for the discovery of drugs for this disease.

Zinc augments the antiviral potential of HCQ/CQ and ivermectin to reduce the risks of more serious outcomes from COVID-19 infection.

Treatments do not replace vaccinations or restrictions, but are practical, effective, and safe means to help to reduce the fatality associated with COVID-19 infection. While no treatment is available and effective for all the current and future variants of COVID-19, treatments reduce the risk of COVID-19 becoming endemic and reduce mortality and collateral damages. The use of Zinc (Zn) for COVID-19 infection is here reviewed. Zn supplementation may help in prevention as well as during the administration of therapies. Zn supplementation reduces the risks of serious outcomes from Covid19 infection. Evidence also suggests that Zn helps in treatments of COVID-19 infection if taken in conjunction with antiviral drugs. The literature supports the use of Zn, with improvements towards a lower risk ranging from 37% in late treatment, RR 0.63 CI [0.53-0.74], to 78% in sufficiency, RR 0.22 CI [0.05-0.96].

Novel antiviral effects of chloroquine, hydroxychloroquine, and green tea catechins against SARS CoV-2 main protease (Mpro) and 3C-like protease for COVID-19 treatment.

OBJECTIVES: Coronaviruses are globally emerging viruses that threaten our health care systems and have become a popular pandemic around the world. This causes a sudden rise in positive coronavirus cases and related deaths to occur worldwide, representing a significant health hazard to humans and the economy. METHODS: We examined predominantly catechins of green tea include epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), and drugs of chloroquine (CQ), and hydroxychloroquine (HCQ) appearing to reveal anti-viral activities. Data were collected from PubMed, Google Scholar, and Science Direct databases. To investigate the role of antiviral effects (CQ and HCQ), green tea catechins, beneficial use of convalescent plasma; covaxin in COVID-19 patients faced a dangerous healthiness issue. Computational docking analysis has been used for this purpose. RESULTS: The lead compounds are EGCG and ECG act as potential inhibitors bind to the active site region of the HKU4-CoV 3CL protease and M-Pro protease enzymes of coronavirus. Conclusions: SARS-COV-2 is a pathogen of substantial vigour concern and the review unveils the role of catechins associated with many viral diseases. We suggested that the function of green tea catechins, novel drugs of CQ, and HCQ exhibit antiviral activities against positive-sense single-stranded RNA viruses (CoVs).

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

Massive Nonfatal Hydroxychloroquine Ingestion in a Pediatric Patient.

BACKGROUND: Hydroxychloroquine overdose is rare but potentially lethal. Hydroxychloroquine overdose symptoms are characterized by central nervous system toxicity, cardiac toxicity, and hypokalemia. Recommended treatment consists of epinephrine, high-dose diazepam, and careful potassium repletion. Few pediatric hydroxychloroquine overdoses have been reported. CASE REPORT: We describe a 14-year-old girl who ingested 10 g (172 mg/kg) of hydroxychloroquine. She developed tachycardia, hypotension, and hypokalemia. She was intubated and treated with diazepam and epinephrine infusions and potassium supplementation. Her serum hydroxychloroquine concentration obtained 10 h after ingestion was 13,000 ng/mL (reference range 500-2000 ng/mL). The patient made a full medical recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pediatric hydroxychloroquine overdoses are reported rarely, and the toxic and lethal doses of hydroxychloroquine ingestion have not been established. This case of a teenaged patient who ingested 10 g of hydroxychloroquine and survived provides additional information that may be used to help establish toxic and lethal doses of ingestion.

Contribution of Meliaceous plants in furnishing lead compounds for antiplasmodial and insecticidal drug development.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria remains one of the greatest threats to human life especially in the tropical and sub-tropical regions where it claims hundreds of thousands of lives of young children every year. Meliaceae represent a large family of trees and shrubs, which are widely used in African traditional medicine for the treatment of several ailments including fever due to malaria. The in vitro and in vivo antiplasmodial as well as insecticidal investigations of their extracts or isolated compounds have led to promising results but to the best of our knowledge, no specific review on the traditional uses, phytochemistry of the antiplasmodial, insecticidal and cytotoxic lead compounds and extracts of Meliaceae plants has been compiled. AIMS: To review the literature up to 2021 on the Meliaceae family with antiplasmodial, insecticidal and cytotoxic activity. MATERIALS AND METHODS: A number of online libraries including PubMed, Scifinder, Google Scholar and Web of Science were used in searching for information on antiplasmodial metabolites from Meliaceous plants. The keywords Meliaceae, malaria, Plasmodium, Anopheles and antiplasmodial were used to monitor and refine our search without language restriction. RESULTS: The phytochemical investigations of genera of the family Meliaceae led to the isolation and characterization of a wide range of structural diversity of compounds, 124 of which have been evaluated for their antiplasmodial potency against 11 chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. A total of 45 compounds were reported with promising insecticidal potentials against two efficient vector species, Anopheles stephensi Liston and A. gambiae Giles. Limonoids were the most abundant (51.6%) reported compounds and they exhibited the most promising antiplasmodial activity such as gedunin (3) which demonstrated an activity equal to quinine or azadirachtin (1) displaying promising larvicidal, pupicidal and adulticidal effects on different larval instars of A. stephensi with almost 100% larval mortality at 1 ppm concentration. CONCLUSION: Studies performed so far on Meliaceae plants have reported compounds with significant antiplasmodial and insecticidal activity, lending support to the use of species of this family in folk medicine, for the treatment of malaria. Moreover, results qualified several of these species as important sources of compounds for the development of eco-friendly pesticides to control mosquito vectors. However, more in vitro, in vivo and full ADMET studies are still required to provide additional data that could guide in developing novel drugs and insecticides.

Melatonin mitigates Chloroquine-induced defects in porcine immature Sertoli cells.

Chloroquine (CQ) could function as a lysosomotropic agent to inhibit the endolysosomal trafficking in the autophagy pathway, and is widely used on malarial, tumor and recently COVID-19. However, the effect of CQ treatment on porcine immature Sertoli cells (iSCs) remains unclear. Here we showed that CQ could reduce iSC viability in a dose-dependent manner. CQ treatment (20 µM) on iSCs for 36h could elevate oxidative stress, damage mitochondrial function and promote apoptosis, which could be partially rescued by melatonin (MT) (10 nM). Transcriptome profiling identified 1611 differentially expressed genes (DEGs) (776 up- and 835 down-regulated) (20 µM CQ vs. DMSO), mainly involved in MAPK cascade, cell proliferation/apoptosis, HIF-1, PI3K-Akt and lysosome signaling pathways. In contrast, only 467 (224 up- and 243 down-regulated) DEGs (CQ + MT vs. DMSO) could be found after MT (10 nM) addition, enriched in cell cycle, regulation of apoptotic process, lysosome and reproduction pathways. Therefore, the partial rescue effects of MT on CQ treatment were confirmed by multiple assays (cell viability, ROS level, mitochondrial function, apoptosis, and mRNA levels of selected genes). Collectively, CQ treatment could impair porcine iSC viability by deranging the signaling pathways related to apoptosis and autophagy, which could be partially rescued by MT supplementation.

Targeting autophagy with natural products to prevent SARS-CoV-2 infection.

Autophagy is a catabolic process that maintains internal homeostasis and energy balance through the lysosomal degradation of redundant or damaged cellular components. During virus infection, autophagy is triggered both in parenchymal and in immune cells with different finalistic objectives: in parenchymal cells, the goal is to destroy the virion particle while in macrophages and dendritic cells the goal is to expose virion-derived fragments for priming the lymphocytes and initiate the immune response. However, some viruses have developed a strategy to subvert the autophagy machinery to escape the destructive destiny and instead exploit it for virion assembly and exocytosis. Coronaviruses (like SARS-CoV-2) possess such ability. The autophagy process requires a set of proteins that constitute the core machinery and is controlled by several signaling pathways. Here, we report on natural products capable of interfering with SARS-CoV-2 cellular infection and replication through their action on autophagy. The present study provides support to the use of such natural products as adjuvant therapeutics for the management of COVID-19 pandemic to prevent the virus infection and replication, and so mitigating the progression of the disease.

Comparative in vivo antimalarial activities of aqueous and methanol extracts of MAMA powder - A herbal antimalarial preparation.

ETHNOPHARMACOLOGICAL RELEVANCE: The choice of extraction solvent is a significant consideration in ethnomedicine as optimal extraction could influence the bioactivity of the herbal medicinal product. AIM OF STUDY: This study investigated the possible influence of the choice of solvents (methanol and water) for extracting MAMA Powder (MP) against Plasmodium berghei-infected mice to optimize its antimalarial activity and for developing other pharmaceutical dosage forms. MATERIALS AND METHODS: Aqueous and methanol extracts of MP, obtained through the decoction and soxhlet methods, respectively, were subjected to liquid chromatography-mass spectroscopy (LC-MS) for their respective fingerprints. The antimalarial activities of the methanol and aqueous extracts (12.5-100 mg/kg) were evaluated orally using the chemosuppressive test model on chloroquine-sensitive Plasmodium berghei-infected mice. The methanol extract was subjected to the established infection and prophylactic antimalarial tests with chloroquine (10 mg/kg) and pyrimethamine (1.25 mg/kg) as positive controls, respectively. The aqueous extract was investigated in chloroquine-resistant P. berghei using the chemosuppressive (12.5-800 mg/kg) and established infection (25-400 mg/kg) antimalarial models. RESULTS: The LC-MS fingerprints of both aqueous and methanol extracts revealed similar indole alkaloid contents. Chemosuppressive activity of the aqueous extract (75.3%) was significantly (p < 0.05) higher than the methanol extract (67.6%). In the chloroquine-resistant P. berghei infection experiments, the aqueous extract (400 mg/kg) exhibited significant parasite clearance (72%). CONCLUSION: The study concluded that the water extract with higher antimalarial activity could be optimized for chloroquine-resistant malaria and can thus facilitate the production of liquid and solid dosage forms.

Complex analysis of the personalized pharmacotherapy in the management of COVID-19 patients and suggestions for applications of predictive, preventive, and personalized medicine attitude.

AIMS: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. METHODS: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. RESULTS: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. CONCLUSION: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

Phytocompounds of Rheum emodi, Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor: In Silico Approach.

COVID-19, the disease caused by SARS-CoV-2, has been declared as a global pandemic. Traditional medicinal plants have long history to treat viral infections. Our in silico approach suggested that unique phytocompounds such as emodin, thymol and carvacrol, and artemisinin could physically bind SARS-CoV-2 spike glycoproteins (6VXX and 6VYB), SARS-CoV-2 B.1.351 South Africa variant of Spike glycoprotein (7NXA), and even with ACE2 and prevent the SARS-CoV-2 binding to the host ACE2, TMPRSS2 and neutrapilin-1 receptors. Since Chloroquine has been looked as potential therapy against COVID-19, we also compared the binding of chloroquine and artemisinin for its interaction with spike proteins (6VXX, 6VYB) and its variant 7NXA, respectively. Molecular docking study of phytocompounds and SARS-CoV-2 spike protein was performed by using AutoDock/Vina software. Molecular dynamics (MD) simulation was performed for 50ns. Among all the phytocompounds, molecular docking studies revealed lowest binding energy of artemisinin with 6VXX and 6VYB, with Etotal -10.5 KJ mol-1 and -10.3 KJ mol-1 respectively. Emodin showed the best binding affinity with 6VYB with Etotal -8.8 KJ mol-1and SARS-CoV-2 B.1.351 variant (7NXA) with binding energy of -6.4KJ mol-1. Emodin showed best interactions with TMPRSS 2 and ACE2 with Etotal of -7.1 and -7.3 KJ mol-1 respectively, whereas artemisinin interacts with TMPRSS 2 and ACE2 with Etotal of -6.9 and -7.4 KJ mol-1 respectively. All the phytocompounds were non-toxic and non-carcinogenic. MD simulation showed that artemisinin has more stable interaction with 6VYB as compared to 6VXX, and hence proposed as potential phytochemical to prevent SARS-CoV-2 interaction with ACE-2 receptor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40495-021-00259-4.