Treatment of Local AnestheticInduced Cardiotoxicity Using Drug Scavenging Nanoparticles

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Treatment of Local Anesthetic-Induced
Cardiotoxicity Using Drug Scavenging Nanoparticles

• Journal Club Presentation Sept. 2006
• Kelly Shinkaruk

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Morey et al

• Basic science research paper
• Undertaken to determine the ability of emulsion
  based nanoparticles to remove Bupivicaine
  molecules from various solutions and compared to
  a standardized macroemulsion
• The hypothesis was that nanoparticles would more
  effectively partition local anesthetics than
  would a macroemulsion

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Morey et al

• Initially, a nanoparticle emulsion was
  synthesized as described in a previous paper (von
  Corswant, C Thoren, P Engstrom, S. J. Pharm
  Sci. 1998, 88, 1071)
• Intralipid, a commercially available
  macroemulsion (Baxter) derived from soybean
  phosphatidylcholine was obtained for use as the
  control lipid emulsion
• The particle population diameter densities were
  analyzed using a submicron particle size analyzer

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Morey et al

• The mean diameters of the nano- and
  macroemulsions were compared using a three
  parameter Gaussian distribution equation
• Each emulsion was found to be normally
  distributed and significantly different

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Morey et al

• There are three parts in this particular
  experiment
• The initial part was used to determine several
  binding parameters of nanoemulsion or
  macroemulsion for bupivacaine
• The second part then went on to analyze the
  extraction of bupivacaine from human blood
  samples
• Finally, the last part looked at the extent to
  which the nanoemulsion attenuated the
  cardiotoxicity bupivacaine caused in guinea pig
  heart

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Extraction of Bupivacaine in PBS

• Bupivacaine was spiked into PBS solution (the
  composition of which is defined in the article)
  and samples containing three concentrations were
  made
• Then the nanoemulsion and macroemulsions were
  added to the samples, allowed to equilibrate and
  then the emulsions were removed by
  ultrafiltration
• Finally, the amount of bupivacaine sequestered by
  each emulsion was analyzed and the nanoemulsion
  was found to have sequestered a greater fraction
  of bupivacaine

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Attenuation of Cardiotoxicity in Guinea Pig Heart

• Using guinea pig hearts, the QRS interval was
  measured as a representation of the summation of
  all sodium ionic currents in the ventricles
• An n5 for each of the nanoemulsion and
  macroemulsion groups was used
• Bupivacaine was noted to increase the QRS
  interval for both groups of hearts

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Attenuation (cont)

• Treatment of the intoxicated hearts with the
  emulsions was found to significantly reduce the
  QRS interval
• The effect of the nanoemulsion was significantly
  greater and more rapid
• In fact, the difference between the two sets of
  emulsions was greater than expected based on the
  initial experiments

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Extraction of Bupivicaine from Human Blood

• In this part, bupivacaine was spiked into blood
  samples
• Once equilibration was attained, the plasma was
  separated from the cells and was centrifuged to
  obtain a protein/particle free supernatant
• The extraction of bupivacaine was analyzed and
  found to be extracted to a greater extent based
  on increasing concentrations of nanoemulsion

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Critical Analysis

• The author clearly defines a research problem and
  explains its significance with regards to the
  practice of medicine
• The author addresses core issues and variables
  furthermore, he defines specialized terminology
• An small but adequate literature review is
  included and past research into the field of
  nanotechnology is sited

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Critical Analysis (2)

• A clear hypothesis is stated
• We hypothesize that smaller emulsion particles
  (ie nanoemulsions) will even more effectively
  partition local anesthetics from an aqueous
  environment into the lipid core or onto the
  surface interface.

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Critical Analysis - Methodology

• Methodology is outlined in each of the three
  parts of the study
• No limitations are noted by the author
• All solutions/samples used are outlined and the
  method in which guinea pig hearts are obtained is
  noted as a reference
• all instruments used in the study are adequately
  described
• The methods for measuring the results are clearly
  outlined and easy to understand

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Critical Analysis - Results

• The results for each part of the study are
  clearly presented though graphs were only given
  for the third part
• The research objectives are addressed
• The graphs utilized are easy to decipher and
  clearly demonstrate the differences between nano
  and macroemulsions

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Critical Analysis - Discussion

• The discussion does not appear under its own
  heading thereby making it difficult to localize
  in the text
• The results do, in fact, validate the authors
  hypothesis
• Only one local anesthetic was tested in this
  study and the author clearly identifies that this
  is a limitation but indicates that further
  research should be undertaken

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Critical Analysis Discussion

• The author suggests that this research could be
  further applied to include nanoemulsions for the
  detoxification of other classes of drugs
• The author does not suggest that this research
  should alter current practice

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Critical Analysis Personal Perspectives

• I believe that this research is very applicable
  in this age of increasing use of regional
  anesthetic techniques
• The research is relevant and touches on a field
  that is in its infancy but promises to
  revolutionize the way in which medical
  professionals deal with drug overdose

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Critical Analysis Personal Perspectives

• As this study was basic science oriented, it
  provides an excellent background for further
  research ultimately leading to clinical trials
• The difficulty is that clinical trials will be
  unethical to undertake in RCT in true overdose
  situations therefore, inevitably, the use of
  nanoparticles in acute overdose situations will
  rely on anecdotal evidence

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Critical Analysis Personal Perspectives

• In conclusion, I feel that this research is
  incredibly relevant and, given the significant
  mortality associated with bupivicaine toxicity,
  it would be reasonable to administer a
  nanoemulsion in acute situations