title: Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats.
abstract: BACKGROUND
  Danshensu is an active water-soluble component from Salvia Miltiorrhiza, which has been demonstrated holding multiple mechanisms for the regulation of cardiovascular system. However, the relative contribution of danshensu to its multiple cardiovascular activities remains largely unknown.
  
  
  OBJECTIVE
  To develop an artificial neural network (NN) model simultaneously characterizing danshensu pharmacokinetics and multiple cardiovascular activities in acute myocardial infarction (AMI) rats. The relationship between danshensu pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated using contribution values.
  
  
  METHODS
  Danshensu was intraperitoneally injected at a single dose of 20mg/kg to AMI rats induced by coronary artery ligation. Plasma levels of danshensu, cardiac troponin T (cTnT), total homocysteine (Hcy) and reduced glutathione (GSH) were quantified. A back-propagation NN model was developed to characterize the PK and PD profiles of danshensu, in which the input variables contained time, area under plasma concentration-time curve (AUC) of danshensu and rat weights (covariate). Relative contribution of input variable to the output neurons was evaluated using neuron connection weights according to Garson's algorithm. The kinetics of contribution values was also compared and was validated using bootstrap resampling method.
  
  
  RESULTS
  Danshensu exerted significant cTnT-lowering, Hcy- and GSH-elevating effect, and these marker profiles were well captured by the trained NN model. The calculation of relative contributions revealed that the effect of danshensu on the PD marker could be ranked as cTnT>GSH>Hcy, while the effect of AMI disease on the PD marker could be ranked in the following order: cTnT>Hcy>GSH. The activity of transsulfuration pathway was quite obvious under the AMI state.
  
  
  CONCLUSIONS
  NN is a powerful tool linking PK and PD profiles of danshensu with multiple cardioprotective mechanisms, it provides a simple method for identifying and ranking relative contribution to the multiple therapeutic effects of the drug.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, No. 24, Tongjia Lane, Jiangsu Province, Nanjing 210009, PR China.
authors.forename: Yuan-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Wan-Wen
authors.initials: WW
authors.lastname: Cao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Bo-Bo
authors.initials: BB
authors.lastname: Chang
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Yang
authors.forename: Xiao-Quan
authors.initials: XQ
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004365:Drugs, Chinese Herbal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D007773:Lactates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D016571:Neural Networks, Computer; D008517:Phytotherapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D020107:Troponin T / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D004365:Drugs, Chinese Herbal; D007773:Lactates; D020107:Troponin T; D006710:Homocysteine; C035055:3,4-dihydroxyphenyllactic acid; D005978:Glutathione