COVID-19 challenges and its therapeutics.

COVID-19, an infectious disease, has emerged as one of the leading causes of death worldwide, making it one of the severe public health issues in recent decades. nCoV, the novel SARS coronavirus that causes COVID-19, has brought together scientists in the quest for possible therapeutic and preventive measures. The development of new drugs to manage COVID-19 effectively is a challenging and time-consuming process, thus encouraging extensive investigation of drug repurposing and repositioning candidates. Several medications, including remdesivir, hydroxychloroquine, chloroquine, lopinavir, favipiravir, ribavirin, ritonavir, interferons, azithromycin, capivasertib and bevacizumab, are currently under clinical trials for COVID-19. In addition, several medicinal plants with considerable antiviral activities are potential therapeutic candidates for COVID-19. Statistical data show that the pandemic is yet to slow down, and authorities are placing their hopes on vaccines. Within a short period, four types of vaccines, namely, whole virus, viral vector, protein subunit, and nucleic acid (RNA/DNA), which can confer protection against COVID-19 in different ways, were already in a clinical trial. SARS-CoV-2 variants spread is associated with antibody escape from the virus Spike epitopes, which has grave concerns for viral re-infection and even compromises the effectiveness of the vaccines. Despite these efforts, COVID-19 treatment is still solely based on clinical management through supportive care. We aim to highlight the recent trends in COVID-19, relevant statistics, and clinical findings, as well as potential therapeutics, including in-line treatment methods, preventive measures, and vaccines to combat the prevalence of COVID-19.

Migration of epoxidized soybean oil from polyvinyl chloride/polyvinylidene chloride food packaging wraps into food simulants.

Epoxidized soybean oil (ESBO) has been used in polyvinyl chloride (PVC)/polyvinylidene chloride (PVDC) food packaging cling film as a plasticizer and stabilizer. The aim of this study was to investigate the migration of ESBO from PVC/PVDC cling film, based on gas chromatography mass spectrometry (GC-MS). The specific migration of ESBO was evaluated using various food simulants (water, 4% acetic acid, 50% ethanol and n-heptane) for PVC and PVDC wrap products. ESBO did not migrate into water and 4% acetic acid for all the tested samples. However, it was released into 50% ethanol and n-heptane in several PVC/PVDC wraps, with maximum migration levels of 38.4 ± 0.7 and 37.4 ± 0.8 µg/mL, respectively. These results demonstrate that ESBO is capable of being released from PVC/PVDC wrap into amphiphilic/oily food and its migration should be regularly monitored.

Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine.

The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects of H. helix extract on cytochrome P450 (CYP) enzyme-mediated metabolism to predict the potential for herb-drug interactions. A cocktail probe assay was used to measure the inhibitory effect of CYP. H. helix extracts were incubated with pooled human liver microsomes or CYP isozymes with CYP-specific substrates, and the formation of specific metabolites was investigated to measure the inhibitory effects. H. helix showed significant inhibitory effects on CYP2C8, CYP2C19 and CYP2D6 in a concentration-dependent manner. In recombinant CYP2C8, CYP2C19 and CYP2D6 isozymes, the IC50 values of the extract were 0.08 ± 0.01, 0.58 ± 0.03 and 6.72 ± 0.22 mg/mL, respectively. Further investigation showed that H. helix extract has a positive time-dependent inhibition property on both CYP2C8 and CYP2C19 with IC50 shift value of 2.77 ± 0.12 and 6.31 ± 0.25, respectively. Based on this in vitro investigation, consumption of herbal medicines or dietary supplements containing H. helix extracts requires careful attention to avoid any CYP-based interactions.

Evaluation of Herb-Drug Interactions of Hovenia dulcis Fruit Extracts.

BACKGROUND: Hovenia dulcis (Rhamnaceae) fruits are popularly used as herbal medicines or dietary supplements in Asian countries due to functions such as liver protection and detoxification from alcohol poisoning. Accordingly, it is very likely for dietary supplemental products, including H. dulcis fruit extracts, to be taken with prescription drugs. OBJECTIVE: In this study, possible food-drug interactions involving H. dulcis fruit extracts were evaluated based on the inhibition of cytochrome P450 (CYP) enzyme activity. MATERIAL AND METHODS: The water extract of H. dulcis fruit extracts was incubated in human liver microsomes with CYP-specific substrates. The formation of the CYP-specific metabolites was measured using liquid chromatography-tandem mass spectrometry. RESULTS: H. dulcis fruit extracts showed negligible effects on seven CYP isozyme activities at all concentrations tested. CONCLUSION: This result suggests that H. dulcis fruit extracts may have minimal pharmacokinetic interactions with coadministered drugs through the modulation of CYP enzymes. SUMMARY: Food-drug interactions involving H. dulcis fruit extracts were evaluated.The inhibition of CYPs by H. dulcis extracts was tested.H. dulcis extracts showed negligible effects on CYP activities.H. dulcis extracts may have minimal pharmacokinetic interactions with co-administered drugs. Abbreviations Used: CYP: cytochrome P450 enzymes, HPLC: High performance liquid chromatography, LC-MS/MS : liquid chromatography-tandem mass spectrometry, MRM: multiple-reaction monitoring.

Inhibitory Effects of Garcinia cambogia Extract on CYP2B6 Enzyme Activity.

This study assessed the inhibitory effects of Garcinia cambogia extract on the cytochrome P450 enzymes in vitro. G. cambogia extract was incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes and recombinant CYP2B6 isozyme, and the formation of the marker metabolites was measured to investigate the inhibitory potential on cytochrome P450 enzyme activities. The results showed that G. cambogia extract has significant inhibitory effects on CYP2B6 activity in a concentration-dependent manner. Furthermore, the inhibition was potentiated following preincubation with NADPH, indicating that G. cambogia extract is a time-dependent inhibitor of CYP2B6. Meanwhile, hydroxycitric acid, the major bioactive ingredient of G. cambogia extract, did not exhibit significant inhibition effects on cytochrome P450 enzyme activities. G. cambogia extract could modulate the pharmacokinetics of CYP2B6 substrate drugs and lead to interactions with those drugs. Therefore, caution may be required with respect to concomitant intake of dietary supplements containing G. cambogia extract with CYP2B6 substrates.

Determination of eurycomanone in rat plasma using hydrophilic interaction liquid chromatography-tandem mass spectrometry for pharmacokinetic study.

In this study, a rapid, sensitive, and reliable hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method for the determination of eurycomanone in rat plasma was developed and validated. Plasma samples were pretreated with a protein precipitation method and quercitrin was used as an internal standard (IS). A HILIC silica column (2.1 × 100 mm, 3 µm) was used for hydrophilic-based chromatographic separation, using the mobile phase of 0.1% formic acid with acetonitrile in gradient elution at a flow rate of 0.25 mL/min. Precursor-product ion pairs for multiple-reaction monitoring were m/z 409.1 → 391.0 for eurycomanone and m/z 449.1 → 303.0 for IS. The linear range was 2-120 ng/mL. The intra- and inter-day accuracies were between 95.5 and 103.4% with a precision of <4.2%. The developed method was successfully applied to the pharmacokinetic analysis of eurycomanone in rat plasma after oral dosing with pure compound and E. longifolia extract. The Cmax and AUC0-t , respectively, were 40.43 ± 16.08 ng/mL and 161.09 ± 37.63 ng h/mL for 10 mg/kg eurycomanone, and 9.90 ± 3.97 ng/mL and 37.15 ± 6.80 ng h/mL for E. longifolia extract (2 mg/kg as eurycomanone). The pharmacokinetic results were comparable with each other, based on the dose as eurycomanone.

An ultra-high-performance liquid chromatography-tandem mass spectrometric method for the determination of hederacoside C, a drug candidate for respiratory disorder, in rat plasma.

Hederacoside C is a principal bioactive pharmaceutical ingredient of Hedera helix leaf extracts. H. helix extracts have long been used in folk medicine for the treatment of respiratory disorders. Currently, hederacoside C is investigated as a promising candidate for the treatment of respiratory diseases. In this study, an accurate, sensitive, rapid, and reliable bioanalytical method was developed for the determination of hederacoside C in rat plasma using ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). For sample preparation, plasma proteins were precipitated with 0.1% acetic acid in acetonitrile. Waters UPLC BEH C18 (2.1mm I.D.×100mm, 1.7µm) column was used for chromatographic separation. A gradient elution of mobile phases consisting of 0.02% acetic acid in distilled water (solvent A) and 0.02% acetic acid in acetonitrile (solvent B) was used at a flow rate of 0.3mL/min. The multiple reaction monitoring (MRM) mode was used for mass spectrometric detection; the MRM transitions were m/z 1219.7→m/z 469.2 for hederacoside C and m/z 1108.3→m/z 221.2 for ginsenoside Rb1 (internal standard) in the negative ionization mode. A calibration curve was constructed in the range of 10-1000ng/mL. The intra- and inter-day precision and accuracy were within 5%. The developed UPLC-MS/MS method was successfully applied in a pharmacokinetic study of hederacoside C in rats. Hederacoside C was quickly but inadequately absorbed from the gastrointestinal tract of rats resulting in extremely low bioavailability and relatively slow clearance.

Review on a Traditional Herbal Medicine, Eurycoma longifolia Jack (Tongkat Ali): Its Traditional Uses, Chemistry, Evidence-Based Pharmacology and Toxicology.

Eurycoma longifolia Jack (known as tongkat ali), a popular traditional herbal medicine, is a flowering plant of the family Simaroubaceae, native to Indonesia, Malaysia, Vietnam and also Cambodia, Myanmar, Laos and Thailand. E. longifolia, is one of the well-known folk medicines for aphrodisiac effects as well as intermittent fever (malaria) in Asia. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery. Its bark is mostly used as a vermifuge, while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever. Mostly, the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling. The roots are also used as an aphrodisiac, antibiotic, appetite stimulant and health supplement. The plant is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, ß-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignan, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. Among these phytoconstituents, quassinoids account for a major portion of the E. longifolia root phytochemicals. An acute toxicity study has found that the oral Lethal Dose 50 (LD50) of the alcoholic extract of E. longifolia in mice is between 1500-2000 mg/kg, while the oral LD50 of the aqueous extract form is more than 3000 mg/kg. Liver and renal function tests showed no adverse changes at normal daily dose and chronic use of E. longifolia. Based on established literature on health benefits of E. longifolia, it is important to focus attention on its more active constituents and the constituents' identification, determination, further development and most importantly, the standardization. Besides the available data, more evidence is required regarding its therapeutic efficacy and safety, so it can be considered a rich herbal source of new drug candidates. It is very important to conserve this valuable medicinal plant for the health benefit of future generations.

A Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantitation of 10 Bioactive Components in Rhus verniciflua Extracts.

The purpose of this study was to develop a simultaneous method to quantify 10 bioactive compounds in Rhus verniciflua extracts using high-performance liquid chromatography-tandem mass spectrometry. The chromatographic separation was performed using a C18 column under gradient elution with 0.1% formic acid and acetonitrile as the mobile phase solvents. The analytes were detected in the negative-ion mode using multiple-reaction monitoring detection with an electrospray ionization interface. The calibration curves for all the analytes showed good linearity (r(2) >0.997) over the concentration range of 1-1,000 ng/mL. The recovery values were within 89.53-110.14%, and the intra- and interday coefficients of variation were <4.86% for all the tested compounds. The developed method was successfully applied to a quality assessment of the R. verniciflua extract samples.

In Vitro Evaluation of the Effects of Eurycoma longifolia Extract on CYP-Mediated Drug Metabolism.

Eurycoma longifolia (Simaroubaceae) is a popular folk medicine that has traditionally been used in Southeast Asia as an antimalarial, aphrodisiac, antidiabetic, and antimicrobial and in antipyretic remedies. This study evaluates the effects of Eurycoma longifolia extract on cytochrome P450 (CYP) enzyme-mediated drug metabolism to predict the potential for herb-drug interactions. Methanolic extract of E. longifolia root was tested at concentrations of 1, 3, 10, 30, 100, 300, and 1000 µg/mL in human liver microsomes or individual recombinant CYP isozymes. The CYP inhibitory activity was measured using the cocktail probe assay based on liquid chromatography-tandem mass spectrometry. E. longifolia showed weak, concentration-dependent inhibition of CYP1A2, CYP2A6, and CYP2C19. The inhibitory effects on these CYP isozymes were further tested using individual recombinant CYP isozymes, showing IC50 values of 324.9, 797.1, and 562.9 µg/mL, respectively. In conclusion, E. longifolia slightly inhibited the metabolic activities of CYP1A2, CYP2A6, and CYP2C19 but this issue requires careful attention in taking herbal medicines or dietary supplements containing E. longifolia extracts.

Interactions between herbs and antidiabetics: an overview of the mechanisms, evidence, importance, and management.

Complementary and alternative therapies are quickly gaining importance because they are perceived to be free of side effects due to their natural origin. However, herbal remedies are complex mixtures of bioactive entities, which may interact with prescription drugs through pharmacokinetic or pharmacodynamic mechanisms and sometimes result in life-threatening consequences. In particular, diabetes patients are often treated with multiple medications due to different comorbidities, and such patients use antidiabetic medications for their entire lives; thus, it is important to make the public aware of herb interactions with antidiabetic drugs. In this paper, we summarize the reports available on the interaction of herbal remedies with oral hypoglycemic agents and describe mechanisms, preclinical or clinical evidence, importance, and management strategies.