Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

Non-insulin dependent anti-diabetic activity of (2S, 3R, 4S) 4-hydroxyisoleucine of fenugreek (Trigonella foenum graecum) in streptozotocin-induced type I diabetic rats.

The seeds of fenugreek, Trigonella foenum graecum, commonly used as a spice in Middle Eastern countries and widely used in south Asia and Europe, are known to have anti-diabetic properties. They contain an unusual amino acid (2S, 3R, 4S) 4-hydroxyisoleucine (4HO-Ile), so far found only in fenugreek, which has anti-diabetic properties of enhancing insulin secretion under hyperglycaemic conditions, and increasing insulin sensitivity. Here we describe for the first time the anti-diabetic activity of 4HO-Ile in a model of type I diabetes, streptozotocin-treated rats, where levels of insulin are much reduced, by 65%, compared to normal animals. Treatment of diabetic rats with daily doses of 4HO-Ile at 50 mg/kg/day for four weeks could reduce plasma glucose in the diabetic group. Moreover the high levels of lipids (cholesterol, HDL, LDL and triglycerides) and uric acid in the diabetic rats, could be restored to levels found in non-diabetic controls by the treatment with 4HO-Ile. These results demonstrate that 4HO-Ile has significant anti-diabetic activities that are independent of insulin and suggest the potential of 4HO-Ile as an adjunct to diabetes treatment and for type 1 as well as type 2 diabetes.

Antitumor activity of Dioscorea bulbifera L. rhizome in vivo.

Antitumor activities of water extract (fraction A), ethanol extract (fraction B), ethyl acetate extract (fraction C), non-ethyl acetate extract (fraction D) and compound diosbulbin B isolated from Dioscorea bulbifera L. (DB) were investigated in vivo in this present study. The results showed that fractions B and C both decreased tumor weight in S180 and H22 tumor cells bearing mice, while fractions A and D had no such effect. Furthermore, fraction C altered the weight of spleen and thymus, and the amounts of total leukocytes, lymphocytes and neutrophils in tumor-bearing mice. Further results showed that compound diosbulbin B demonstrated anti-tumor effects in the dose-dependent manner at the dosage of 2 to 16 mg/kg without significant toxicity in vivo. Furthermore, on the basis of chemical analysis of the above extracts by high-performance liquid chromatography (HPLC) with a diode array detector (DAD), diosbulbin B was found to be the major antitumor bioactive component of DB. These results suggest that DB has potential anti-tumor effects which may be related to influencing the immune system for the first time, and the compound diosbulbin B is the major antitumor component of DB.

Urinary (1)H-NMR metabonomics study on intervention effects of soya milk in Africans.

Metabonomics is an important tool in understanding the toxicological or therapeutic effects of interventions by analysing metabolic profiles and interpreting complex multi-dimensional spectroscopic/spectrometric data using multivariate data analysis. The objectives of this study were to evaluate the metabolic changes following a short-term 5 day soya milk intervention, and to investigate factors that influence soy-phytoestrogen metabolism focused on Africans based in either UK or Nigeria. (1)H-NMR metabonomics was applied to analyse urine samples collected at four phases I-IV (pre, days 3 and 5, and post) of the soy-intervention from African volunteers (n = 40 in total). Individual proton NMR spectra were visually and statistically assessed using multivariate analyses (MVA): principal component analysis (PCA) and (orthogonal-) partial-least square-discriminant analysis ((O-) PLS-DA). In addition, 22 endogenous metabolites were quantified using a Chenomx NMR suite. The results showed the levels of analysed endogenous metabolites (creatinine adjusted) present ranged from 4 µM to 12 mM with large inter-subject variances in acetate, acetone, lactate and trimethylamine. The MVA results showed high inter-individuality and sampling variances based on PCA score plots, and demonstrated soy metabolism to be significantly influenced by location and gender by both PLS-DA and O-PLS-DA.

A randomized trial of intravenous n-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes.

BACKGROUND: Pharmacokinetic data suggests that the intravenous form of n-acetylcysteine (NAC) may be more effective than the oral formulation in preventing contrast induced nephropathy (CIN). NAC owing to its anti-oxidant properties might be beneficial for patients with acute coronary syndromes (ACS) who are at increased risk for CIN. The aim of this prospective randomized, single-center, double-blind, placebo controlled trial (NCT00939913) was to assess the effect of high-dose intravenous NAC on CIN in ACS patients undergoing coronary angiography and/or percutaneous coronary intervention (PCI). METHODS: We randomized 398 ACS patients scheduled for diagnostic angiography ± PCI to an intravenous regimen of high-dose NAC (1,200 mg bolus followed by 200 mg/hr for 24 hr; n = 206) or placebo (n = 192). The primary end-point was incidence of CIN defined as an increase in serum creatinine concentration ≥ 25% above the baseline level within 72 hr of the administration of intravenous contrast. RESULTS: There was no difference found for the primary end point with CIN in 16% of the NAC group and in 13% of the placebo group (p = 0.40). Change in serum cystatin-C, a sensitive marker for renal function, was 0.046 ± 0.204 in the NAC group and 0.002 ± 0.260 in the control group (p = 0.07). CONCLUSION: In ACS patients undergoing angiography ± PCI, high-dose intravenous NAC failed to reduce the incidence of CIN.

Treatment with Qing'E, a kidney-invigorating Chinese herbal formula, antagonizes the estrogen decline in ovariectomized mice.

A Chinese herbal preparation, Qing'E formula (QEF), has been used clinically for treating osteoporosis in postmenopausal women by virtue of its kidney-invigorating function; however, no evidence base links QEF to estrogen replacement therapy. In this study, we undertake a characterization of estrogenic activity of QEF using an in vivo model of ovariectomized (OVX) mice together with in vitro studies with the MCF-7 cells for further molecular characterization. OVX mice were treated intragastrically with QEF at doses of 0.85, 1.7, and 3.4 g/kg per day for 4 weeks. QEF treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by reversal of uterine atrophy (six-fold increase in uterine weight), reduction in rectal temperature, and increased expression (1.6-fold) of estrogen receptors (ERs) in the uterus. Notably, the largest changes in these three parameters were found at the lowest dose. At the highest dose of QEF, significant changes were found in adrenal gland weight (30% increase), serum estradiol (E(2)) (60% increase), and luteinizing hormone (LH) (17% decrease) compared with untreated OVX controls. The data suggest estrogenic responses induced by QEF show tissue variation that reflects different affinities of ERs for QEF components. QEF could significantly induce luciferase expression (2.7-fold compared with control) from an estrogen response element luciferase reporter and induced expression of ERalpha and ERbeta (1.2-fold and 1.7-fold respectively) in MCF-7 cells. Both activities were inhibited 80-90% by the estrogen antagonist ICI 182,780. This study demonstrates that QEF activity is mediated through estrogenic components and provides an evidence base for QEF treatment of postmenopausal symptoms.

Electrospun shikonin-loaded PCL/PTMC composite fiber mats with potential biomedical applications.

Novel electrospun poly(epsilon-caprolactone) (PCL)/poly(trimethylene carbonate) (PTMC) ultrafine composite fiber mats were prepared and used as drug-carrying materials to encapsulate the herbal medicine shikonin isolated from the plant Lithospermum erythrorhizon Sieb. et Zucc. The PCL/PTMC blended solutions in various ratios (9:1, 7:3, and 5:5, w/w) containing 1 and 5 wt.% shikonin were studied for electrospinning into nanoscale fiber mats. With good drug stability and high drug-loading efficacy, incorporation of shikonin in the polymer media did not appear to influence the morphology of the resulting fibers, as both the drug-free and the shikonin-loaded composite fibers remained unaltered, microscopically. The average diameter of the composite fibers decreased, and the morphology of the fibers became finer with the increasing content of PTMC. In vitro drug release studies demonstrated an initial rapid release of shikonin followed by a plateau after 11 h. It was found that the release behavior could be tailored by the PCL/PTMC blend ratio and drug-loading content. Moreover, the free radical scavenging activity and the antibacterial effects of the shikonin-loaded fiber mats indicated that it could act not only as a drug delivery system but also in the treatment of wound healing or dermal bacterial infections.

Quantitative analysis of total retronecine esters-type pyrrolizidine alkaloids in plant by high performance liquid chromatography.

Pyrrolizidine alkaloids (PAs) are alkaloids which typically contain a necine (7-hydroxy-1-hydroxymethyl-6,7-dihydro-5H-pyrrolizidine) base unit, and they can be found in one third of the higher plants around the world. They are hepatotoxic, mutagenic and carcinogenic and pose a threat to human health and safety. A specific, quick and sensitive method is therefore needed to detect and quantify the PAs sometimes in trace amount in herbs, tea or food products. Based on high performance liquid chromatography with prior derivatization of the alkaloids using o-chloranil and Ehrlich's reagent, we report an improved method for quantitative analysis of the total amount of retronecine esters-type pyrrolizidine alkaloids (RET-PAs) in a plant extract. The total quantitation of RET-PAs is achieved because of a common colored retronecine marker, a 7-ethoxy-1-ethoxylmethyl retronecine derivative, is produced with all the different RET-PAs during the derivatization reaction. The chemical identity of the common retronecine marker was characterized on-line by positive mode electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. The limit of detection using the improved method is 0.26 nmol mL(-1) and the limit of quantitation is 0.79 nmol mL(-1). The advantages of this method are much enhanced sensitivity in detection and quantitation, and, no restriction on the choice of RET-PA as a calibration standard. Application of the developed method to the quantitation of total RET esters-type PAs in Senecio scandens from different regions of China is also reported.

Pharmacokinetics and tissue distribution of gentiopicroside following oral and intravenous administration in mice.

The pharmacokinetics and tissue distribution of Gentiopicroside (GPS), one of the major active components of the Gentiana species of medicinal plants, was studied following oral and intravenous administration in mice. The distribution of GPS in mice after oral and intravenous doses could be fitted to a two-compartments open model. The serum half-life of GPS was 6.1 h and 2.8 h for intravenous and oral administration, respectively. The Tmax of GPS after oral administration was 0.50 h, and the bioavailability was 39.6%. The AUC gradient in individual tissues following intravenous administration was kidney >serum >liver >spleen >lung >thymus >fat >heart >muscle >stomach >intestinal >brain. The MRT gradient was muscle >serum >lung >spleen >lung >intestinal>heart >stomach >brain >liver >thymus >kidney >fat. Overall the data show that GPS could be absorbed rapidly in mice, but with a low bioavailability, and could distribute to tissues extensively, but was generally cleared quickly with short MRTs. The study demonstrates the need for repeated dosage, or better, a slow release formulation as an ideal means of administering GPS.