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XTractor Premium
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• A platform for discovery, analysis and modelling
  of published biomedical facts-updated with
  manually annotated scientific information from
  Pubmed every single day

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Case Study Amitriptyline - Pharmacologic
actions, protein interactions and toxicity
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Target Disease
Xtractor Facts

• Amitriptyline presumably blocks both
  sphingomyelinases and, thus, its use might be a
  novel strategy to treat malaria.
• Amitriptyline did not significantly alter
  intraerythrocytic parasite development but
  significantly (gt/ 1 muM) delayed the increase in
  parasitemia in vitro.
• Most importantly, amitriptyline treatment (1 mM
  in drinking water) resulted in a significant
  delay of parasitemia and death of infected mice.

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Pharmacologic actions
XTractor Facts

• Amitriptyline attenuates interstitial
  inflammation and ameliorates the progression of
  renal fibrosis.
• Sublethal X-irradiation or mycophenolate mofetil,
  treatments that reduce inflammation, were
  comparable to amitriptyline in the reduction of
  interstitial fibrosis and macrophage
  infiltration.
• These studies in animals suggest that
  amitriptyline is worth testing as a therapeutic
  agent that might preserve renal function by
  blocking inflammation and renal fibrosis.Kidney
  International advance online publication, 26
  November 2008 doi10.1038/ki.2008.578.
• Amitriptyline Suppresses Neuroinflammation-depende
  nt Interleukin-10-p38 Mitogen-activated Protein
  Kinase-Heme Oxygenase-1 Signaling Pathway in
  Chronic Morphine-infused Rats.
• CONCLUSIONS These results suggest that the
  antiinflammatory effect of amitriptyline on
  morphine tolerance, probably acting by increasing
  IL-10 expression, is mediated by p38
  mitogen-activated protein kinase heme oxygenase-1
  signal transduction cascade.

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Drug-protein interactions
XTractor Facts

• It was found that OB induced an increase in
  mGluR1a-immunoreactivity (IR), which was
  abolished by AMI treatment in the hippocampus.
• Adecrease of mGluR7-IR was observed in the OB
  group, and the effect was abolished by the
  administration of AMI.
• However, decreases in the level of mGlu2/3 and
  mGlu7 receptors were observed after AMI
  administration.
• Amitriptyline inhibits the activity of the rat
  glutamate transporter EAAT3 expressed in Xenopus
  oocytes.
• CONCLUSIONS Our results suggested that
  amitriptyline at clinically relevant
  concentrations reversibly reduced EAAT3 activity
  via decreasing its maximal velocity of glutamate
  transporting function.
• Here, we hypothesize that AMT activates cardiac
  ryanodine channels (RyR2) causing premature
  Ca(2) release from the sarcoplasmic reticulum
  (SR), a mechanism identified by genetic studies
  as a cause of ventricular arrhythmias and sudden
  cardiac death.

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• Toxicity
• Clearance
• Dosing
• Target prioritization
• Off target effects
• Drug reusability studies
• Mutation/SNP analysis
• Pathway studies
• Disease mechanisms

• XTractor Premium-
• The One stop solution for all your drug discovery
  queries

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