April 27 th 2010 Mary Coan. Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins

April 27 th 2010 Mary Coan

Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins Nanocarrier Biodetoxification Liposomes Nanoemulsions Nanoparticles Macromoleculues Carriers Future Work Conclusion Image: http://www.nature.com/nnano/journal/v3/n3/covers/index.htmlhttp://www.nature.com/nnano/journal/v3/n3/covers/index.html

Introduction Acute intoxications, either accidental or intentional, constitute a major public health problem worldwide Due to the cost burden placed onto the hospital, patient, or the public depending on the healthcare system provided Illicit drug use plays a profoundly large role in number of treated acute intoxication cases Approximately 40% Significant number of deaths are due to over the counter drug overdoses Analgesics Antidepressants Sedatives/hypnotics/antipsychotics Stimulants Cardiovascular Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image; http://www.topnews.in/health/files/cholesterol-lowering-drugs.jpghttp://www.topnews.in/health/files/cholesterol-lowering-drugs.jpg

Introduction Many acute intoxication cases result in life-threatening situations Typical treatment for conscious patients in these cases consists of Emptying the stomach Administering activated charcoal Gastric emptying Whole bowel irrigation Haemodialysis Correction of electrolyte disturbances Adminstering I-V fluids Removal of toxins through extracorporeal procedures Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://eslpod.com/eslpod_blog/wp-content/uploads/2008/02/emergency-1.jpghttp://eslpod.com/eslpod_blog/wp-content/uploads/2008/02/emergency-1.jpg

Introduction Some of the listed treatments can be used on the unconscious Whole bowel irrigation and haemodialysis are generally reserved for eliminating specific life-threatening toxins from the body Antidotes are rarely available and/or exist Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://pencilsatdawn.wordpress.com/2007/07/14/antidote/

Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins Nanocarrier Biodetoxification Liposomes Nanoemulsions Nanoparticles Macromoleculues Carriers Future Work Conclusion Image: http://best.rutgers.edu/files/imagecache/featured_block_1/testtubes_3.JPGhttp://best.rutgers.edu/files/imagecache/featured_block_1/testtubes_3.JPG

Current Standard Detoxification Methods: Administration of an Antidote There are antidotes for specific cases Organophosphate/Carbamate insecticide Atropine Acetaminophen N-Acetylcysteine (NAC)/Mucomyst Narcotic overdose Naloxone/Narcan There are many more antidotes that are specifically for chemical exposure or poisonous bites not for drug overdoses http://www.rphworld.com/viewlink-25090.html Image: http://store.vitaminliving.com/images/uploads/IV_Bag.jpghttp://store.vitaminliving.com/images/uploads/IV_Bag.jpg

Current Standard Detoxification Methods: Administration of an Antidote All of these antidotes can be given via an IV or shot Example of a largely used antidote is Narcan Non-habit forming and causes no long-term side effects Sudden reversal of a heroin high can induce vomiting Supplied to thousands of Heroin addicts by local government programs to reverse a drug overdose Thousands have been saved since the induction of the program in a select few cities http://www.boston.com/news/local/articles/2007/11/02/addicts_to_receive_overdose_antidote/ Image: http://www.abconlinepharmacy.com/ns/imagem.php?masterid=1299

Current Standard Detoxification Methods: Gastric Emptying For patients that swallow any poisonous substance, not including alcohol, the following procedure is typically followed: 1. IV fluids are administered and continued 2. Activated charcoal is administered a) Orally via a black drink, if the patient is awake and alert b) Orally through a tube, if the patient is not awake Adsorbs and eliminates drugs/metabolites that are still present or being secreted in the gastrointestinal track 3. Observe the patient and administer any anti-vomiting medicine as needed http://www.emedicinehealth.com/activated_charcoal/article_em.htm Image: http://www.krider.com/MPj03211260000%5B1%5D.jpghttp://www.krider.com/MPj03211260000%5B1%5D.jpg

Current Standard Detoxification Methods: Gastric Emptying Whole Bowel Irrigation is also used to remove toxins from the entire gastrointestinal tract (GI tract) Flushes the GI tract of everything including any ingested toxins Typically used only for toxins that are not absorbed by activated charcoal Iron Lithium Sustained-release or Enteric-coated Drugs Both procedures can not remove any of the toxins already absorbed into the patients blood stream http://emedicine.medscape.com/article/1413446-overview

Current Standard Detoxification Methods: Gastric Emptying In the case of Ethanol intoxication Gastric Lavage is used to remove the contents of the stomach Used in patients that are not vomiting A tube is passed through the mouth to the stomach followed by sequential administration and removal of small volumes of liquid via suction Can be used in the cases of Drug related intoxication if used within 1 hour of consumption Overdoses can lead to the following if the patient is not treated quickly: Permanent brain/nervous system damage Comas Death Image: http://emptyyourcup.com/blog/uploaded/iStock_000003492238Small_9.jpghttp://emptyyourcup.com/blog/uploaded/iStock_000003492238Small_9.jpg http://wps.prenhall.com/wps/media/objects/737/755395/gastric_lavage.pdf

Current Standard Detoxification Methods: Removal of Toxins Many cases an antidote does not exist and the patient did not orally ingest the drug Only solution is to remove the toxins from the blood stream Hemodialysis is the only readily available procedure to remove toxins from the blood stream Removes substances from the patients blood by passing the blood through a semi-permeable membrane in a bedside dialysis machine Suited for drugs or metabolites that are water soluble low volume of distribution, generally remains in the blood stream not in the organs Molecular weight below 500 g/mol Low plasma protein binding Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Current Standard Detoxification Methods: Removal of Toxins An emerging strategy for removing toxins from the blood stream Injected nanosized particulate carriers (< 1 m) that act as a sink for the toxin When a toxic dose of a chemical enters a patients blood stream, elevation of the patients tissue concentrations above the minimum toxic level (MTL), represented by the blue line, occurs Toxic levels are maintained until the toxic chemical diffuses and/or metabolizes out of the patients tissues (organs) Resulting in a decrease of tissue concentrations (upper curve) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Current Standard Detoxification Methods: Removal of Toxins Nanocarriers absorb the toxin from the blood stream and/or the tissue Allows for the redistribution of the toxic chemical from the peripheral tissues into the blood compartment Reduces tissue exposure to the toxic compound By bringing the tissues concentration below the MTL at a faster rate (lower curve) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Current Standard Detoxification Methods: Removal of Toxins Injected nanocarriers exit the body via the kidneys or the liver Natural excretion of the nanocarriers is acceptable and preferred Saves money, time and reduces the patients risk of surgery Once the toxic chemical is sequestered by the nanocarriers it will not leach back into the body Nanosized carriers can take on different forms Liposomes Nanoemulsions Nanoparticles Macromolecules Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image 1: http://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpg,Image 2: http://www.pharmoscorp.com/development/nanotechnology.html,Image 3: http://radio- weblogs.com/0105910/images/nanoparticles.jpg, Image 4: http://www.rsc.org/ejga/SM/2008/b807696k-ga.gifhttp://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpghttp://www.pharmoscorp.com/development/nanotechnology.htmlhttp://radio- weblogs.com/0105910/images/nanoparticles.jpghttp://www.rsc.org/ejga/SM/2008/b807696k-ga.gif

Current Standard Detoxification Methods: Removal of Toxins Several of the listed nanocarriers can function as detoxifiers Detoxifiers Properties High Specific Surface Area Adjustbale Composition/Surface Porperties Manipulated to optimize uptake and circulation time. Nanocarriers used biodetoxification usually share the same characteristics as those used in drug delivery Except the affinity of the toxic agent to the carrier should be very high to ensure rapid and efficient removal of toxins from the peripheral tissues. Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins Nanocarrier Biodetoxification Liposomes Nanoemulsions Nanoparticles Macromoleculues Carriers Future Work Conclusion http://www.rsc.org/ejga/CP/2010/b914440d-ga.gif

Nanocarrier Biodetoxification There are several parameters of the toxic chemical to be considered in toxicity reversal Molecular weight Ionization constant Affinity for blood proteins (V d ) Half-life Toxicological profile Presence of active metabolites Potential toxicity of metabolites Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.3dchem.com/imagesofmolecules/Cocaine.jpghttp://www.3dchem.com/imagesofmolecules/Cocaine.jpg

Nanocarrier Biodetoxification Most drugs involved in poisoning are weak bases that are characterized by a large V d High protein binding and the presence of active metabolites Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Large V d s can complicate the detoxification procedure Especially in the case of a slow transfer rate of the toxins from the tissues to the blood Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification When drugs bind to blood proteins the extraction efficiency is lowered Less drug is available for capture Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification In most laboratory settings The nanocarrier is administered prior to or within minutes following exposure to the drug In many cases the intoxicated patient is admitted to a hospital 3-4 hours after the drug has entered the patients body Large amounts of the drug may have been converted into active metabolites Some drugs are inactive until contact with a certain bodily fluid, e.g. Silvia, Stomach Acid, Other GI fluids, when they become activated For example, upon oral absorption almost instantaneously 40% of amitriptyline, an antidepressant, is metabolized by the liver into its active demethylated form Nortriptyline Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Schematic representation of the multiple effects of cannabis smoking on basic enzymatic and physiological mechanisms. These effects are mediated by r 9 -THC and possibly by active metabolites, and lead to the development of functional and metabolic tolerance. Image: http://www.unodc.org/images/odccp/bulletin/bull etin_1973-01-01_1_page003_img003_large.gif http://www.unodc.org/images/odccp/bulletin/bull etin_1973-01-01_1_page003_img003_large.gif

Nanocarrier Biodetoxification Injectable nanocarriers need to meet a number of criteria including but not limited to: Innocuousness Circulation time Uptake capacity In order for the injected carrier to be successful Must remain in the blood stream and/or tissues Long enough for the toxic agent to be extracted sufficiently from the blood stream and peripheral tissues Short enough so that the toxic agent isn't leached back into the bloodstream and/or tissues Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification The human bodys response to nanocarriers is very similar to colloids Circulation time of a colloid depends on its hydrodynamic volume, shape and surface properties Spherical colloids, maximum circulation times are obtained for those with diameters between 50200 nm Very small colloids ( 200 nm) are subjected to major uptake by the spleen Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image 1: http://focus.aps.org/story/v20/st21http://focus.aps.org/story/v20/st21

Nanocarrier Biodetoxification Nanocarriers coated with hydrophilic, flexible polymers such as polyethylene glycol (PEG) Slow down the immune system clearance time Improve the half-life in blood Nanocarriers with extracted toxins are generally eliminated from the bloodstream within 24 hr and mostly end up in the liver where the toxic compound is metabolized Most drugs rarely cause any significant liver damage upon acute poisoning Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.technologyreview.com/read_article.aspx?id=17578&ch=nanotech&a=fhttp://www.technologyreview.com/read_article.aspx?id=17578&ch=nanotech&a=f

Nanocarrier Biodetoxification Quickly decreasing tissue concentrations below the toxic threshold requires the drug to ideally be completely and rapidly captured Oil(lipid)-based nanocarriers Selected lipids need to highly compatible with the toxin Many hydrophobic and amphiphilic drugs are poorly soluble in injectable lipids Large amounts of the nanocarrier dose is required to extract the toxic agent Infusing high amounts of lipids may be acceptable in the context of detoxification and potentially saving a life Injecting large doses of nanocarriers (> 1 g/kg or > 5 ml/kg for a typical 20%-lipid emulsion) can slow down the detoxification process Increases the time during which the nanocarrier is administered Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.biotargeting.eu/images/%28master%29_0001.pnghttp://www.biotargeting.eu/images/%28master%29_0001.png

Nanocarrier Biodetoxification Typically the partition coefficient, or the solubility of two solvents, for the oil phase is the main parameter used to eliminate possible mixtures For the uptake of toxic agents by oil-based nanostructures this is not the case Amphiphilic compounds that possess hydrophilic and hydrophobic properties can adsorb at the oil/water interface Adsorption depends on specific surface area Depends on particle size Extraction capacity generally increases with decreasing particle size For the case of amphiphilic charged drugs Adsorption at the interface between the nanocarrier and the drug can be enhanced by adding an oppositely charged component to the nanocarriers surface that interacts electro-statically with the drug Chemically modifying the nanocarrier with specific functional groups can increase drug uptake and improve extraction Example, electron-deficient aromatic rings that bind to compounds with -electron-rich aromatic rings Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification An alternative strategy to optimize extraction is to create an concentration gradient between the inside and outside of the nanocarrier This can be achieved by encapsulating an enzyme that degrades the toxic agent into water-filled vesicular structures Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Toxins diffuse into the carrier Are metabolized by the enzymes Thus more toxic compounds can be pumped into the carrier This system requires The toxic agent to freely permeate the vesicle membranes The entrapped enzyme to remain active for at least a few hours while circulating in the blood Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Optimization of the extraction of ionizable drugs Including weak bases or acids Sequesters the toxic agent into nanosized vesicles by creating a transmembrane pH gradient Similar to the urinary pH manipulation technique Used by clinicians to accelerate excretion of ionizable drugs from the kidneys Neutral low-molecular-weight weak acids and bases can permeate vesicle membranes at much faster rates than their ionized forms This extraction process is very efficient, even for molecules that are highly protein-bound Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification If a vesicle exhibits a pH gradient (acidic or basic for weak bases or acids), the unionized compound diffuses down its concentration gradient into the vesicle interior where it is subsequently ionized and trapped The diffusion of the toxic agents neutral form will continue until the interior buffering capacity is overwhelmed Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Several colloidal carriers have been investigated for detoxification applications over the past two decades Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Nanocarrier Biodetoxification Sizes ranging from a few nanometres (polymers) to half a micrometrer (emulsions in parenteral nutrition) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins Nanocarrier Biodetoxification Liposomes Nanoemulsions Nanoparticles Macromoleculues Carriers Future Work Conclusion

Nanocarrier Biodetoxification: Liposomes Liposomes Spherical vesicles Possess one or more concentric phospholipid bilayer membrane(s) Have been extensively studied for the treatment of intoxications due to organophosphorus agents (OPs) Toxic agents commonly found in agriculture pesticides Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpghttp://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpg

Nanocarrier Biodetoxification: Liposomes First use of liposomes as antidotes for OPs was a follow-up to the work of Way and co-workers Resealed red blood cells served as vesicles to encapsulate the enzymes rhodanese and organophosphorus acid anhydrolase (OPAA) Degrade cyanide and OPs, respectively Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Leung, P. et al. Encapsulation of thiosulfate:cyanide sulfurtransferase by mouse erythrocytes. Toxicol Appl. Pharmacol. 83, 101107 (1986). Pei, L., Petrikovics, I. & Way, J. L. Antagonism of the lethal effects of paraoxon by carrier erythrocytes containing phosphotriesterase. Fundam. Appl. Toxicol. 28, 209214 (1995). Cyanide and/or OPs Rhodanese and/or (OPAA)

Nanocarrier Biodetoxification: Liposomes The approach was later refined by entrapping OPAA in neutral long-circulating PEGylated liposomes Liposomes were chosen to replace the red blood cells in Ways work due to the following factors: Built from non-human- derived material Possible large-scale production Exhibit a greater shelf-life than red blood cells Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Petrikovics, I. et al. Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes. Toxicol. Appl. Pharmacol. 156, 5663 (1999). Petrikovics, I. et al. Comparing therapeutic and prophylactic protection against the lethal effect of paraoxon. Toxicol. Sci. 77, 258262 (2004). Petrikovics, I. et al. Long circulating liposomes encapsulating organophosphorus acid anhydrolase in diisopropylfluorophosphate antagonism. Toxicol. Sci. 57, 1621 (2000). Enviromental SEM image of bilayer construction of several liposomes Image: http://uber-life.net/technology/liposomes.shtmlhttp://uber-life.net/technology/liposomes.shtml

Nanocarrier Biodetoxification: Liposomes Replacing the red blood cells with liposomal OPAA in mice resulted in an efficient detoxifier for Ops However, liposomal OPAA is only effective when administered in prevention cases Prior to intoxication Application of lipomal OPAA after injection of OP, resulted in substantial increase of OP-induced mortality A more probable situation to happen under real conditions of intoxication Although these data confirmed the therapeutic value of liposomal OPAA, they also revealed how important timing is in reversing intoxications Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Petrikovics, I. et al. Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes. Toxicol. Appl. Pharmacol. 156, 5663 (1999). Petrikovics, I. et al. Comparing therapeutic and prophylactic protection against the lethal effect of paraoxon. Toxicol. Sci. 77, 258262 (2004).

Nanocarrier Biodetoxification: Liposomes Previously mentioned, transmembrane pH gradients can help remove low-molecular-weight weak acids or bases from physiological media Mayer et al. used stealth (long-circulating) liposomes with an internal pH of 4 as the detoxifying nanocarrier Administered prior to the injection of a toxic dose of the anti-cancer drug doxorubicin Captured the drug in vivo Decreased its toxicity Maintained the drugs anti-tumor potency The pH gradient was maintained with a decrease of only 1.5 units over 20 hrs following injection Doxorubicin could be sequestered in situ at clinically relevant doses Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, Mayer, L. D., Reamer, J. & Bally, M. B. Intravenous pretreatment with empty pH gradient liposomes alters the pharmacokinetics and toxicity of doxorubicin through in vivo active drug encapsulation. J. Pharm. Sci. 88, 96102 (1999).

Nanocarrier Biodetoxification: Liposomes Mayers study showed that pre-treatment with empty liposomes could improve the pharmacokinetic profiles of drugs Along with their potential as detoxifying agents pH gradient spherulites were investigated by Dr. Babu Dhanikula to counteract an overdose of amitriptyline A type of multilamellar liposome made from uniformly spaced concentric bilayers Amitriptyline is a potentially cardiotoxic antidepressant Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, Babu Dhanikula, A., Lamontagne, D. & Leroux, J. C. Rescue of amitriptyline-intoxicated hearts with nanosized vesicles. Cardiovasc. Res. 74, 480486 (2007). Simard, P., Hoarau, D., Khalid, M. N., Roux, E. & Leroux, J. C. Preparation and in vivo evaluation of PEGylated spherulite formulations. Biochim. Biophys. Acta 1715, 3748 (2005).

Nanocarrier Biodetoxification: Liposomes Isolated hearts were first coated with amitriptyline at a large enough concentration to cause cardio-toxicity Immediate infusion of pH- gradient spherulites resulted the recovery of the heart rate Spherulite concentration in this investigation could be readily achieved in vivo Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, Babu Dhanikula, A., Lamontagne, D. & Leroux, J. C. Rescue of amitriptyline-intoxicated hearts with nanosized vesicles. Cardiovasc. Res. 74, 480486 (2007). Heart-rate recovery after intoxication and addition of a nanocarrier. Overdose of amitriptyline elevates heart rates and brings about deleterious effects on the heart (cardiotoxicity). Isolated rat hearts were infused for 12 min with amitriptyline to cause intoxication and subsequently perfused with pH 7.4 buffer (red squares), pH 7.4 spherulites (black triangles), or pH 3.0 gradient spherulites (green circles) from 15 to 37 min. Perfusion of pH 3.0 gradient spherulites resulted in swift recovery of heart rate to its initial value because the nanocarrier extracted amitriptyline from the heart tissue and the protonated drug was sequestered within the vesicle aqueous core. The black arrows indicate the time during which the difference in heart beats between the pH 3.0 spherulite and pH 7.4 buffer group was statistically significant (p

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April 27 th 2010 Mary Coan. Outline Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins