Deslanoside

Identifying potential entry inhibitors for emerging Nipah virus by molecular docking and chemical-protein interaction network.[Pubmed:31771426]

J Biomol Struct Dyn. 2019 Dec 6:1-18.

Nipah Virus (NiV) is a newly emergent paramyxovirus that has caused various outbreaks in Asian countries. Despite its acute pathogenicity and lack of approved therapeutics for human use, there is an urgent need to determine inhibitors against NiV. Hence, this work includes prospection of potential entry inhibitors by implementing an integrative structure- and network-based drug discovery approach. FDA-approved drugs were screened against attachment glycoprotein (NiV-G, PDB: 2VSM), one of the prime targets to inhibit viral entry, using a molecular docking approach that was benchmarked both on CCDC/ASTEX and known NIV-G inhibitor set. The predicted small molecules were prioritized on the basis of topological analysis of the chemical-protein interaction network, which was inferred by integrating the drug-target network, NiV-human interaction network, and human protein-protein interaction network. A total of 17 drugs were predicted to be NiV-G inhibitors using molecular docking studies that were further prioritized to 3 novel leads - Nilotinib, Deslanoside and Acetyldigitoxin - on the basis of topological analysis of inferred chemical-protein interaction network. While Deslanoside and Acetyldigitoxin belong to an already known class of anti-NiV inhibitors, Nilotinib belongs to Benzenoids chemical class that has not been reported hitherto for developing anti-NiV inhibitors. These identified drugs are expected to be successful in further experimental evaluation and therefore could be used for anti-Nipah drug discovery. Apart, we also obtained various insights into the underlying chemical-protein interaction network, based on which several important network nodes were predicted. The applicability of our proposed approach was also demonstrated by prospecting for anti-NiV phytochemicals on an independent dataset.Communicated by Ramaswamy H. Sarma.

[Effects of cardiac support on delayed resuscitation in extensively burned patients with shock].[Pubmed:29374921]

Zhonghua Shao Shang Za Zhi. 2018 Jan 20;34(1):8-13.

Objective: To explore the effects of cardiac support on delayed resuscitation in extensively burned patients with shock. Methods: Clinical data of 62 extensively burned patients with shock on admission, admitted to the 159th Hospital of PLA (hereinafter referred to as our hospital) from January 2012 to January 2017, were retrospectively analyzed. They were divided into cardiac support group (n=35) and control group (n=27) according to the use of Deslanoside and ulinastatin. All patients were treated with routine fluid resuscitation based on the formula of the Third Military Medical University till post injury hour (PIH) 48. Patients in cardiac support group were given slow intravenous injection of Deslanoside which was added in 20 mL 100 g/L glucose injection with first dose of 0.4 to 0.6 mg, 0.2 to 0.4 mg per 6 to 8 h, no more than 1.6 mg daily, and slow intravenous injection of 1x10(5)U ulinastatin which was added in 100 mL 50 g/L glucose injection, once per 12 h. Other treatments of patients in the two groups followed the same conventional procedures of our hospital. The following data of the two groups of patients were collected. (1) The data of urine volume per hour within PIH 48, heart rate, mean arterial pressure (MAP), central venous pressure (CVP), blood lactic acid, base excess, hematocrit, and albumin at PIH 48 were recorded. (2) The input volumes of electrolyte, colloid within the first and second 24 hours post burn and the total fluid input volumes within PIH 48 were recorded. (3) The data of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, beta(2)-microglobulin, urea nitrogen, and creatinine at PIH 48 were recorded. (4) The complications including cardiac failure, pulmonary edema, pleural effusion, seroperitoneum, renal failure, sepsis, and death were also recorded. Data were processed with independent sample ttest, Fisher's exact test, Pearson chi-square test, or continuous correction chi-square test. Results: (1) There were no statistically significant differences in urine volume within PIH 48, heart rate, MAP, CVP, hematocrit, or albumin at PIH 48 between the patients of two groups (t=0.150, 0.488, 0.805, 0.562, 1.742, 0.696, P>0.05). While the levels of blood lactic acid and base excess were respectively (4.2+/-2.2) and (-4.3+/-2.0) mmol/L in patients of cardiac support group, which were significantly better than (5.9+/-1.7) and (-6.0+/-3.1) mmol/L in patients of control group (t=3.249, 2.480, P<0.05 or P<0.01). (2) There was no statistically significant difference in input volume of colloid within the first 24 hours post burn between the patients of two groups (t=0.642, P>0.05). The input volume of electrolyte within the first 24 hours post burn, the input volumes of electrolyte and colloid within the second 24 hours post burn, and the total fluid input volume within PIH 48 of patients in cardiac support group were significantly less than those in control group (t=2.703, 4.223, 3.437, 2.515, P<0.05 or P<0.01). (3) The levels of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, beta(2)-microglobulin, urea nitrogen, and creatinine of patients in cardiac support group at PIH 48 were significantly lower than those in control group (t=3.066, 3.963, 3.225, 2.943, 2.431, 3.084, 4.052, 2.915, 3.353, P<0.05 or P<0.01). (4) The occurrences of pleural effusion and seroperitoneum and mortality of patients in cardiac support group were significantly lower than those in control group (chi(2)=5.514, 6.984, 4.798, P<0.05 or P<0.01). There were no statistically significant differences in cardiac failure, pulmonary edema, renal failure, and sepsis between the patients of two groups [chi(2)=1.314 (sepsis), P>0.05]. Conclusions: The cardiotonic and cardiac protection treatments in delayed resuscitation of extensively burned patients with shock contribute to improving the cellular anonic metabolism, reducing the volume of fluid resuscitation, and mitigating the ischemic and hypoxic damage to organs, so as to lay foundation for decreasing further complication incidences and mortality.

Ontology-based systematical representation and drug class effect analysis of package insert-reported adverse events associated with cardiovascular drugs used in China.[Pubmed:29061976]

Sci Rep. 2017 Oct 23;7(1):13819.

With increased usage of cardiovascular drugs (CVDs) for treating cardiovascular diseases, it is important to analyze CVD-associated adverse events (AEs). In this study, we systematically collected package insert-reported AEs associated with CVDs used in China, and developed and analyzed an Ontology of Cardiovascular Drug AEs (OCVDAE). Extending the Ontology of AEs (OAE) and NDF-RT, OCVDAE includes 194 CVDs, CVD ingredients, mechanisms of actions (MoAs), and CVD-associated 736 AEs. An AE-specific drug class effect is defined to exist when all the drugs (drug chemical ingredients or drug products) in a drug class are associated with an AE, which is formulated as a new proportional class level ratio ("PCR") = 1. Our PCR-based heatmap analysis identified many class level drug effects on different AE classes such as behavioral and neurological AE and digestive system AE. Additional drug-AE correlation tests (i.e., class-level PRR, Chi-squared, and minimal case reports) were also modified and applied to further detect statistically significant drug class effects. Two drug ingredient classes and three CVD MoA classes were found to have statistically significant class effects on 13 AEs. For example, the CVD Active Transporter Interactions class (including reserpine, indapamide, digoxin, and Deslanoside) has statistically significant class effect on anorexia and diarrhea AEs.

Conventional Acupuncture for Cardiac Arrhythmia: A Systematic Review of Randomized Controlled Trials.[Pubmed:28432528]

Chin J Integr Med. 2018 Mar;24(3):218-226.

OBJECTIVE: To exam the effect and safety of conventional acupuncture (CA) on cardiac arrhythmia. METHODS: Nine medical databases were searched until February 2016 for randomized controlled trials. Heterogeneity was measured by Cochran Q test. Meta-analysis was conducted if I(2) was less than 85% and the characteristics of included trials were similar. RESULTS: Nine qualified studies involving 638 patients were included. Only 1 study had definitely low risk of bias, while 7 trials were rated as unclear and 1 as high. Meta-analysis of CA alone did not have a significant benefit on response rate compared to amiodarone in patients with atrial fibrillation (Af) and atrial flutter (AF) [relative risk (RR): 1.09; 95% confidence interval (CI): 0.79-1.49; P=0.61; I(2)=61%, P=0.11]. However, 1 study with higher methodological quality detected a lower recurrence rate of Af in CA alone as compared with sham acupuncture plus no treatment, and benefits on ventricular rate and time of conversion to normal sinus rhythm were found in CA alone group by 1 study, as well as the response rate in CA plus Deslanoside group by another study. Meta-analysis of CA plus anti-arrhythmia drug (AAD) was associated with a significant benefit on the response rate when compared with AAD alone in ventricular premature beat (VPB) patients (RR, 1.19, 95% CI: 1.05-1.34; P=0.005; I(2)=13%, P=0.32), and an improvement in quality-of-life score (QOLS) of VPB also showed in 1 individual study. Besides, a lower heart rate was detected in the CA alone group by 1 individual study when compared with no treatment in sinus tachycardia patients (MD-21.84 [-27.21,-16.47]) and lower adverse events of CA alone were reported than amiodarone. CONCLUSIONS: CA may be a useful and safe alternative or additive approach to AADs for cardiac arrhythmia, especially in VPB and Af patients, which mainly based on a pooled estimate and result from 1 study with higher methodological quality. However, we could not reach a robust conclusion due to low quality of overall evidence.

A sensitive method for digoxin determination using formate-adduct ion based on the effect of ionization enhancement in liquid chromatograph-mass spectrometer.[Pubmed:25544010]

J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Jan 26;978-979:138-44.

A sensitive and rapid method based on formate-adduct ion detection was developed and fully validated for digoxin determination in rat plasma. For LC/MS/MS detection with formate-adducts as precursor ions, transitions of m/z 825.5-->779.9 for digoxin and m/z 809.5-->763.4 for the internal standard (digitoxin) were monitored in negative mode. To investigate the impact of formic acid on the mass response and method sensitivity, a formic acid concentration range of 0-0.1% (0, 0.0005%, 0.002%, 0.01%, 0.1%, v/v) was evaluated. A concentration of 0.002% gave the highest sensitivity, which was 16- to 18-fold higher than deprotonated ions, and was designated as the contribution giving the strongest ionization enhancement and adduction. A number of parameters were then varied in order to optimize the method, and a limit of quantitation (LOQ) at 0.2 ng/mL was reached with an injection volume of 5 muL, a total run time of 3 min, and 0.1 mL of rat plasma. A calibration curve was plotted over the range 0.2-50 ng/mL (R(2)=0.9998), and the method was successfully applied to study pharmacokinetics in rat following a single oral administration of digoxin (0.05 mg/kg). Four additional steroid saponins (digitoxin, Deslanoside, ginsenoside Rg1 and Rb1) were investigated to assess the impact of formic acid on the mass response of steroid saponins. Compounds with a conjugated lactonic ring in their structures such as digoxin, digitoxin and Deslanoside tended to form stable formate-adduct ions more easily. The LC/MS/MS method developed here is therefore well suited for the quantification of steroid saponins that are difficult to deprotonate using other MS approaches.

Effects of acute administration of ethanol on experimental arrhythmia.[Pubmed:23282204]

Chin J Physiol. 2012 Oct 31;55(5):307-13.

Many studies have shown that the relationship between alcohol consumption and most cardiovascular diseases is U-shaped, with nondrinkers and heavier drinkers having higher risks than moderate drinkers. However, the association between cardiac arrhythmias and acute alcohol consumption is not well understood. We set up several experimental arrhythmia animal models to examine the effects of acute administration of ethanol on arrhythmia. The results showed 0.4, 0.8 and 1.6 g/kg ethanol consumption obviously delayed the onset time of atrial fibrillation (AF) (P < 0.05 or P < 0.01) and increased the survival rates on acetylcholine-CaCl(2)-induced AF in mice. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption significantly delayed the onset time of ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) (P < 0.01), and 0.4 and 0.8 g/kg ethanol consumption increased the survival rates on CaCl(2)-induced arrhythmia in rats. Ethanol (0.4 g/kg) essentially increased the cumulative dosage of aconitine required to CA (P < 0.05), and 0.8 g/kg, 1.6 g/kg ethanol reduced the cumulative aconitine dosage to induce VT, VF and CA (P < 0.05 or P < 0.01) on aconitine-induced arrhythmia in rats. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption remarkably increased the cumulative dosage of Deslanoside to induce ventricualr premature contraction (P < 0.01) on Deslanoside-induced arrhythmia in guinea pigs. Collectively, our results indicate that low concentrations of ethanol had anti-arrhythmic effect on experimental arrhythmia, and high concentrations of ethanol may aggravated the occurrence of experimental arrhythmia.

Characteristics of deslanoside-induced modulation on jejunal contractility.[Pubmed:23139604]

World J Gastroenterol. 2012 Nov 7;18(41):5889-96.

AIM: To characterize the dual effects of Deslanoside on the contractility of jejunal smooth muscle. METHODS: Eight pairs of different low and high contractile states of isolated jejunal smooth muscle fragment (JSMF) were established. Contractile amplitude of JSMF in different low and high contractile states was selected to determine the effects of Deslanoside, and Western blotting analysis was performed to measure the effects of Deslanoside on myosin phosphorylation of jejunal smooth muscle. RESULTS: Stimulatory effects on the contractility of JSMF were induced (45.3% +/- 4.0% vs 87.0% +/- 7.8%, P < 0.01) by Deslanoside in 8 low contractile states, and inhibitory effects were induced (180.6% +/- 17.8% vs 109.9% +/- 10.8%, P < 0.01) on the contractility of JSMF in 8 high contractile states. The effect of Deslanoside on the phosphorylation of myosin light chain of JSMF in low (78.1% +/- 4.1% vs 96.0% +/- 8.1%, P < 0.01) and high contractile state (139.2% +/- 8.5% vs 105.5 +/- 7.34, P < 0.01) was also bidirectional. Bidirectional regulation (BR) was abolished in the presence of tetrodotoxin. Deslanoside did not affect jejunal contractility pretreated with the Ca(2+) channel blocker verapamil or in a Ca(2+)-free assay condition. The stimulatory effect of Deslanoside on JSMF in a low contractile state (low Ca(2+) induced) was abolished by atropine. The inhibitory effect of Deslanoside on jejunal contractility in a high contractile state (high Ca(2+) induced) was blocked by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSION: Deslanoside-induced BR is Ca(2+) dependent and is related to cholinergic and adrenergic systems when JSMF is in low or high contractile states.

Simultaneous analysis of cardiac glycosides in blood and urine by thermoresponsive LC-MS-MS.[Pubmed:21076957]

Anal Bioanal Chem. 2011 Jan;399(3):1141-9.

A new thermoresponsive polymer separation column was applied to simultaneous analysis of four cardiac glycosides (CGs) being widely used for the treatment of arrhythmias and heart failure in human blood and urine. This column is composed of an N-isopropylacrylamide polymer, the surface of which undergoes a reversible alteration from hydrophilic to hydrophobic by changing temperature. The chromatographic separation and retention times can be easily be controlled by adjusting the column temperature. As the column temperature was changed from 50 to 10 degrees C over 8 min, five CGs, including Deslanoside, digoxin, methyldigoxin, digitoxin, and digitoxigenin (internal standard) were better resolved. Using these LC conditions, we analyzed four CGs in human whole blood and urine simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Validation data as functions of recovery rates, linearity, accuracy, and precision were carefully tested; all were generally satisfactory. The detection limits for the four CGs in both matrices were 0.2-0.3 ng/mL. The method was applied to analysis of methyldigoxin and its main metabolite digoxin in whole blood and urine samples obtained from a deceased person in actual autopsy case. To our knowledge, this is the first report describing an LC-MS-MS method using a thermoresponsive column for analysis of drug(s). The inclusion of the thermoresponsive column in an LC-MS-MS technique seems to extend the possibility for simultaneous analysis of compounds of different properties, such as hydrophobic precursors and their hydrophilic metabolites in biological samples within limited analysis times.

Study on cardioactive effects of brazilein.[Pubmed:16319518]

Pharmacology. 2006;76(2):76-83.

Brazilein (6a,7-dihydro-3,6a,10-trihydroxy-benz[b]indeno[1,2-d]pyran-9(6H)-one) is a compound obtained in a large amount from Caesalpinia sappan ethanol extracts with a high purity of about 98%. In isolated cardiac tissues, we found that brazilein exhibited a positive inotropic action in a concentration-dependent manner with little effect on heart rate and coronary perfusion. To study its possible mode of action, isolated rat hearts were treated with propranolol. This treatment did not alter the cardiotonic effect of brazilein, suggesting that this effect does not involve stimulation of beta-adrenoceptors. On the other hand, an analysis of the interaction between Na(+),K(+)-ATPase and brazilein was carried out. Albino guinea pig erythrocytes (mainly alpha1-Na(+),K(+)-ATPase isoforms) enriched with Na(+),K(+)-ATPase isoforms were utilized to compare the inhibition promoted by brazilein with that of classical inhibitors such as the cardiac glycoside Deslanoside. Analysis of inhibition curves revealed that unlike Deslanoside, brazilein had a relatively low affinity for erythrocyte isoforms and failed to completely inhibit the Na(+),K(+)-ATPase activity. The extent of the maximum inhibition rate was about 50%. The inhibitory effect of brazilein was not antagonized by 10 mmol/l K(+), as observed with Deslanoside. Electrocardiogram research in vivo showed that brazilein did not induce the ventricular arrhythmias observed with Deslanoside, suggesting that brazilein might have a less adverse effect and higher therapeutic index than cardiac glycosides. In light of all the above-mentioned observations, it can be concluded that brazilein, a molecule with a non-steroidal skeleton, produced its positive inotropic effect through inhibiting Na(+),K(+)-ATPase and could thus serve as a structural paradigm to develop new inotropic drugs.

Digitalis inhibits and furosemide does not change the in vitro phagocytic function of neutrophils of healthy subjects.[Pubmed:12946440]

Int Immunopharmacol. 2003 Oct;3(10-11):1439-45.

This work evaluated the in vitro influence of digitalis and furosemide on the phagocytic function of neutrophils of healthy individuals. Phagocytosis of Saccharomyces cerevisiae by peripheral blood neutrophils of 20 healthy individuals was assessed in the absence or presence of Deslanoside or furosemide. The Wilcoxon test was employed to compare the data expressed as median and extreme values. Digitalis reduced the number of yeasts ingested by neutrophils (2.23, 1.23-4.01 versus 1.89, 0.87-2.79; p = 0.019). It did not influence the percentage of these cells engaged in phagocytosis, although there was a tendency for reduction (71%, 23-95% versus 57%, 8-93%; p = 0.11), which resulted in decreasing the phagocytic index from 192 (30-381) to 125 (10-218) (p = 0.028). Furosemide had no significant influence on the number of S. cerevisiae phagocytosed (2.23, 1.23-4.01 versus 1.96, 0.70-4.45; p = 0.89), the percent of phagocytosing neutrophils (71%, 23-95% versus 73%, 9-96%; p = 0.86) and the phagocytic index (192, 30-381 versus 152, 10-428; p = 0.95). These findings indicate the inhibitory influence of digitalis on in vitro neutrophil phagocytic function of healthy subjects, and suggest that this effect might impair the innate immune defense response. On this basis, they could contribute to improve digitalis therapy and advise that this drug class should not be associated with other drugs that may also impair the immune function, or might be used with caution or even avoided in subjects with infections.

Successful resuscitation of serious bupivacaine intoxication in a patient with pre-existing heart failure.[Pubmed:12514153]

Can J Anaesth. 2003 Jan;50(1):62-6.

PURPOSE: In dogs intoxicated with bupivacaine, clonidine is effective to treat conduction disturbances and dobutamine corrects myocardial depression. We report the case of a patient who experienced severe bupivacaine cardiotoxicity and who was treated successfully using these medications. CLINICAL FEATURES: In a patient with pre-existing heart failure a surgical procedure to fix a humeral fracture was necessary. Preoperatively, heart failure was controlled with transcutaneous nitroglycerin and iv Deslanoside. A bupivacaine bolus was administered iv accidentally (a mixture of bupivacaine 75 mg, 15 micro g clonidine). The patient developed nodal rhythm with extreme bradycardia, severe shock and convulsions. Seizures were controlled with thiopentone/succinylcholine. Epinephrine iv boluses (0.1 mg x 3) restored blood pressure (BP) to 50/30 mmHg and heart rate (HR) to 60 (nodal rhythm). Following 75 micro g clonidine iv, BP rose to 90/70 and HR to 90 min. Cardiac rhythm reverted to sinus rhythm with first degree atrio-ventricular block. Echocardiography showed hyperkinesia and relative hypovolemia that was controlled with iv administration of terlipressin and glucagon. Subsequent dobutamine infusion stabilized hemodynamic conditions. It was decided to proceed with surgery using a midazolam/sufentanil based general anesthetic. In the intensive care unit, recovery, extubation and weaning from the dobutamine infusion were realized within 16 hr of the event. CONCLUSIONS: In this patient with preoperative heart failure, clonidine was effective to treat bupivacaine induced conduction disturbances. Epinephrine and dobutamine were effective to treat myocardial depression and terlipressin effectively controlled vasodilatation.

[Anesthesia for cesarean section in a Marfan patient with complicated aortic dissection].[Pubmed:12471788]

Ann Fr Anesth Reanim. 2002 Oct;21(8):672-5.

We report the anaesthetic management of a 32-year-old pregnant women with aortic dissection and Marfan syndrome for caesarean section. The patient has presented at 31 weeks gestation of a first pregnancy an aortic dissection that required an emergency aortic replacement. Three years later, she presented at 31 weeks gestation with aortic dissection, mitral valve dysfunction and acute pulmonary oedema. She was treated in intensive care unit with Deslanoside, diuretic and twice a day echographic examination. Delivery was planned by caesarean section after haemodynamic stabilisation on the sixth day. Combined spinal and epidural anaesthesia was performed after monitoring. The initial intrathecal injection of bupivacaine, morphine and fentanyl provided rapid onset of analgesia. Epidural anaesthesia was used with diluted lidocaine and fentanyl boluses. With appropriate preoperative care and monitoring, uneventful combined spinal and epidural anaesthesia for Caesarean section was achieved in a patient with Marfan syndrome in the presence of aortic dissection complicated by mitral valve dysfunction and acute pulmonary oedema.