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Gold Standard Physiological
Measurements and Novel Drug
Delivery Methods – Session 2
Sponsored by:
Dr. Robert Doyle
Profes...
InsideScientific is an online educational environment
designed for life science researchers. Our goal is to aid in
the sha...
Synthetic, Structural, and Mechanistic
Investigations of Vitamin B12 Conjugates of
the Anorectic Peptide PYY3-36
Professor...
Obesity
CDC Behavioral Risk Factor Surveillance System, 2012, http://www.cdc.gov/obesity/data/adult.html
PYY and Appetite Regulation
• PYY is a 36 aa intestinal hormone that belongs to
the pancreatic polypeptide family1
• Synth...
PYY3-36 in Obesity Research
• Peripheral administration of PYY3-36 into rodents1
and primates,2 including humans,3 has res...
Vitamin B12 (B12/Cobalamin)
1 Nexø et al. Nat. Rev. Gastroentero. 2012, 9 (6), 345-354.
2 Russell-Jones et al. Bioconjugat...
B12 Dietary Uptake Pathway
1 Nexø et al. Nat. Rev. Gastroentero. 2012, 9 (6), 345-354.
2 Alpers et al. Pharm. Biotechnol. ...
Hypothesis
Conjugation of B12 to PYY3-36 will have
positive pharmacodynamic and
pharmacokinetic effects in vivo upon
subcu...
Specific Aims
1. Synthesize and characterize B12-PYY3-36
conjugates via a series of B12-alkyne precursors
2. Test B12-PYY3...
Synthesis of B12-Alkyne Precursors
Doyle et al. Synlett. 2012, 23 (16), 2363-2366.
Yield (%) MW (g/mol)
84 1406
79 1420
75...
Structure and Modification of PYY3-36
PDB: 2DF0
N term. β-Turn α helix C term.
I K P E A P G E D A S P E E L N R Y Y A S L...
Synthesis of B12-PYY3-36 Conjugates (1-3)
n
1
2
3
Yield (%) MW (g/mol)
93 5481
95 5495
90 5509
TBTA: tris[(1-benzyl-1H-1,2...
Representative Purification (1)
RP-HPLC: C18 analytical column, flow rate 1 mL/min, 25 °C, UV detection at 280 nm.
A: 0.1%...
Aim 2: Binding, selectivity, and
agonism of the Y2 (anorectic) and
Y1 (orectic) receptors in vitro
Goals
1. Construct and ...
1 Jacoby et al. ChemMedChem 2006, 1 (8), 760-782.
2 Herzog et al. PNAS 1992, 89 (13), 5794-5798.
GPCR Signal Transduction
...
CICR Signaling and Detection
λex: 340 and 380 nm
λem: 510 nm
1 https://www.lifetechnologies.com/order/catalog/product/F120...
Y2 Receptor-Stimulated CICR
1 vs. 2 vs. 3
Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122.
PYY3-36
1
2
3
Compound ...
Y1 Receptor-Stimulated CICR
PYY1-36
PYY3-36
2
Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122.
Compound EC50 (nM)
...
Y1 vs. Y2 Receptor
Nygaard et al. Biochemistry 2006, 45 (27), 8350-8357.
PYY1-36
PYY3-36
PYY1-36
PYY3-36
Synthesis of Null Conjugate B12-PYYC36 (4)
SPDP: 3-(2-pyridylthio)propionic acid N-hydroxysuccinimide ester
Doyle et al. C...
Y2-Receptor Stimulated CICR
PYY3-36 & 2 vs. PYYC36 & 4
1 Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122.
2 Peders...
Aim 3: In vivo feeding studies (sc)
with PYY3-36, 2, and 4 in rats*
Goals
1. Optimize dosing in lean (Sprague Dawley) male...
Dose Escalation Study with 2
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
Thermal/Solution Stability of 2
*All samples ran at 300 nM
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
Implanting Microinfusion Pumps
Dosing Schedule
Baseline
PYY3-36
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
Baseline
2
Baseline
PYY3-36
Food Intake Trends
4
2
PYY3-36
4
2
PYY3-36
* P < 0.05
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
Food Intake Trends
23.7% reduction in food intake due to treatment with 2 and a 13.2% reduction in food
intake due to trea...
* P < 0.05
** P < 0.01
Body Weight Gain
1 Henry et al. Endocrinology 2015, 156 (5), DOI: en.2014-1825.
2 Reidelberger et a...
Pulses of Drugs and Time of Action
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
PYY3-36 B12-PYY3-36PYY3-36 B1...
In Vivo Uptake Studies
Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
** *
**
10 nmol/kg 6
10 nmol/kg PYY3-36
1...
PYY3-36: Mechanisms of Action
BRAIN GUT BLOOD
Vagal nerve carries sensory
information from the Y2
receptors in the gut to
...
C-Fos Immunohistochemistry
PYY3-36 2 4 Saline
Y2 Receptor Activation
!
!Y2 Receptor Activation
Vagus Nerve
1 Doyle R.P. et...
Design of NOTA-2
Doyle R.P. et al. unpublished data.
64Cu-NOTA-2 PET Scan
Administered Dose recovered in brain for 2 vs. PYY3-36. (2-tailed p=0.08). 15 μCi
injected dose 64Cu-...
Zucker Rats: FI Trends
Average
FoodIntake(g/day)
Baseline 4d Treatment
0
10
20
30
40
B12-PYY3-36
PYY3-36
*
*
2
PYY3-36
* P...
Zucker Rats: BW Trends
BodyWeight(g)
Day 0 Day 10 Day 20 Day 30
750
800
850
900
950
1000
B12-PYY3-36
PYY3-36
Baseline Trea...
Conclusions and Summary
** *
**
10 nmol/kg 6
10 nmol/kg PYY3-36
10 nmol/kg 2
10 nmol/kg PYY3-36
4 2 PYY3-36
2
PYY3-36
4
Av...
Future Work: SUPER PYY!
GLP1-R agonism
Y2-R biased agonism
Doyle R.P. et al. unpublished data; Patent Filed Sept. 2015
Thank you to our event sponsor
Innovative drug infusion technology for laboratory animals.
Dr. Robert Doyle
rpdoyle@syr.edu
Thank You!
For additional information on iPrecio
infusion pumps and Innovative drug
infus...
Gold Standard Physiological Measurements and Novel Drug Delivery Methods - Session 2
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Gold Standard Physiological Measurements and Novel Drug Delivery Methods - Session 2

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A 2-part webinar for scientists interested in novel drug delivery methods for basic research, drug discovery and development. Learn about novel infusion technologies and how challenges in physiological monitoring and drug delivery are being overcome by implantable and programmable devices.

Session 2: Synthetic, Structural, and Mechanistic Investigations of Vitamin B12 Conjugates of the Anorectic Peptide PYY3-36

Presenter: Dr. Robert Doyle, Syracuse University & SUNY, Upstate Medical University

Dr. Robert Doyle talks about how vitamin B12 conjugation of Peptide YY3-16 decreases food intake compared to native Peptide – YY3-36 in male rats. Learn how challenges to peptide-based therapies, such as rapid clearance, ready degradation by hydrolysis/proteolysis and poor intestinal uptake and/or a need for blood brain barrier transport can be overcome by using vitamin B12 in the subcutaneously administered drug delivery device iPrecio.

Publié dans : Sciences
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Gold Standard Physiological Measurements and Novel Drug Delivery Methods - Session 2

  1. 1. Gold Standard Physiological Measurements and Novel Drug Delivery Methods – Session 2 Sponsored by: Dr. Robert Doyle Professor of Chemistry & Biology, Syracuse University
  2. 2. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.
  3. 3. Synthetic, Structural, and Mechanistic Investigations of Vitamin B12 Conjugates of the Anorectic Peptide PYY3-36 Professor Robert P. Doyle Syracuse University & SUNY, Upstate Medical University November 12th 2015
  4. 4. Obesity CDC Behavioral Risk Factor Surveillance System, 2012, http://www.cdc.gov/obesity/data/adult.html
  5. 5. PYY and Appetite Regulation • PYY is a 36 aa intestinal hormone that belongs to the pancreatic polypeptide family1 • Synthesized and released by specialized enteroendocrine cells (L cells)1 • PYY has two main receptors, Y1 (orectic effect) and Y2 (anorectic effect)2 • The active anorectic form of PYY is a truncated form known as PYY3-36 2 1 Ekblad et al. Peptides 2002, 23 (2), 251–261. 2 Batterham et al. Nature 2002, 418 (6898), 650−654.
  6. 6. PYY3-36 in Obesity Research • Peripheral administration of PYY3-36 into rodents1 and primates,2 including humans,3 has resulted in an observed reduction in food intake • Infusion of PYY3-36 into obese individuals (BMI ≥ 30)4 results in a reduced caloric intake comparable to individuals of lower BMI3 • Oral delivery of PYY3-36 via vitamin B12 has been established by the Doyle group in clinically relevant levels (> 180 pg/mL) in rodents5 1 Batterham et al. Nature 2002, 418 (6898), 650−654. 2 Moran et al. Am. J. Physiol.: Regul. Integr. Comp. Physiol. 2005, 288 (2), R384−R388. 3 Batterham et al. N. Engl. J. Med. 2003, 349 (10), 941–948. 4 http://www.nhlbi.nih.gov/health/health-topics/topics/obe/diagnosis.html 5 Doyle et al. J. Med Chem. 2011, 54 (24), 8707-8711.
  7. 7. Vitamin B12 (B12/Cobalamin) 1 Nexø et al. Nat. Rev. Gastroentero. 2012, 9 (6), 345-354. 2 Russell-Jones et al. Bioconjugate Chem. 1995, 6 (1), 34-42. 3 Russell-Jones et al. Bioconjugate Chem. 1999, 10 (6), 1131-1136. onsible ceptor- ntial for only the cfactor issyn- omach, sidethe highly transcobalamin synthesis.Theaffectedchilddisplaysfew symptomsat birth,but within monthsaseveredeficiency developsand,if left untreated,it leadstolifelongimpair- mentsdueto neurological damage.23–27 Several different kindsof mutationsleading to alack of transcobalamin havebeen identified, includingdeletionsand mutations resultingin erroneousRNA editing.23–27 Haptocorrin isheavilyglycosylated and isexpressed in many,but not all,mammals.28 In humans,haptocorrin is b Cytosol Mitochondrion FolatePurines, pyrimidines TH- Folate5-methyl TH- Methionine synthase Methylcobalamin Homocysteine Methionine Adenosylcobalamin Methylmalonyl-CoA Succinyl-CoA Methylmalonyl-CoA mutase B12 structure. The core of B12 consists of a corrin ring that encircles a n atoms from the corrin ring, as well as to a nitrogen atom from a ositioned below the plane of the corrin ring and a variable group (R) able group can be occupied by several ligands, including a hydroxyl, matically active cofactor carries either a methyl or a 5'-deoxadenosyl efers to all variants of the vitamin, unless otherwise stated. two distinct enzymatic processes: the conversion of homocysteine to he conversion of methylmalonyl-CoA to succinyl-CoA by mitochondrial inked to folate metabolism because the methyl group transferred to thyl tetrahydrofolate to tetrahydrofolate. Tetrahydrofolate is essential
  8. 8. B12 Dietary Uptake Pathway 1 Nexø et al. Nat. Rev. Gastroentero. 2012, 9 (6), 345-354. 2 Alpers et al. Pharm. Biotechnol. 1999, 12, 493-520. 3 Banerjee et al. J. Biol. Chem. 2013, 288 (19), 13186-13193. 4 Doyle et al. Exp. Opin. Drug. Deliv. 2010, 8 (1), 127-140. B12$ HC$ B12$ HC$ B12$ B12$ B12$ B12$ B12$ B12$ IF$ IF$ CB$ AM$ B12$ IF$ CB$ AM$ to$ileum$ to$stomach$ Kd$≈$0.01$pM$ $ to$duodenum$ $pH$>$5$ ! Dietary$source$of$ B12$is$broken$in$ mouth$releasing$ B12;$bound$by$HC$ ileal$enterocyte$B12$ TCII$ MRP1$ B12$ TCII$ ?$ B12$ TCII$ CD320$ MG$ Kd$≈$1.0$pM$ Kd$≈$0.005$pM$ pH$<$3$ B12$ Average$daily$ uptake$of$B12$is$ about$1O5$μg3$ Dietary source of B12 is broken down in the mouth, releasing B12; bound by HC
  9. 9. Hypothesis Conjugation of B12 to PYY3-36 will have positive pharmacodynamic and pharmacokinetic effects in vivo upon subcutaneous (sc) administration
  10. 10. Specific Aims 1. Synthesize and characterize B12-PYY3-36 conjugates via a series of B12-alkyne precursors 2. Test B12-PYY3-36 conjugatesfor binding, selectivity, and agonism of the Y2 (anorectic) and Y1 (orectic) receptors in vitro 3. Perform sc in vivo feeding studies with B12-PYY3- 36 conjugates
  11. 11. Synthesis of B12-Alkyne Precursors Doyle et al. Synlett. 2012, 23 (16), 2363-2366. Yield (%) MW (g/mol) 84 1406 79 1420 75 1434 EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideHOBt: hydroxybenzotriazole
  12. 12. Structure and Modification of PYY3-36 PDB: 2DF0 N term. β-Turn α helix C term. I K P E A P G E D A S P E E L N R Y Y A S L R H Y L N L V T R Q R Y Pederson et al. J. Pept. Sci. 2009, 15 (11), 753-759.
  13. 13. Synthesis of B12-PYY3-36 Conjugates (1-3) n 1 2 3 Yield (%) MW (g/mol) 93 5481 95 5495 90 5509 TBTA: tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
  14. 14. Representative Purification (1) RP-HPLC: C18 analytical column, flow rate 1 mL/min, 25 °C, UV detection at 280 nm. A: 0.1% TFA in H2O, B: MeCN, Method: 10% B to 35% B over 25 minutes. tR = 23.1 min 5456.008 MALDI-ToF MS: 1:1 sample:matrix ratio, CHCA matrix, 10 mg/mL, 50:50 H2O:MeCN with 0.1% TFA. Expected m/z: 5481 (parent) 5455 (-CN) 0 200 400 600 800 1000 1200 Intens.[a.u.] 2000 4000 6000 8000 10000 m/z
  15. 15. Aim 2: Binding, selectivity, and agonism of the Y2 (anorectic) and Y1 (orectic) receptors in vitro Goals 1. Construct and optimize calcium-induced calcium release (CICR) assay via Y2 and Y1 receptors to test activity of conjugates 1-3 vs. PYY3-36 and PYY1-36 2. Confirm Y2 receptor agonism with synthesis and in vitro characterization of a “null” conjugate
  16. 16. 1 Jacoby et al. ChemMedChem 2006, 1 (8), 760-782. 2 Herzog et al. PNAS 1992, 89 (13), 5794-5798. GPCR Signal Transduction Plasma Membrane Gq-coupled Gs-coupled Gi-coupled αq *αq αs *αs αi βββ γ γγ PIP2 IP3 + DAG + + PLCβ + Adenylate Cyclase ATP IP3 Ca++ Ca++ + PKC β γ -- cAMP + PKA *αi Transcrip on factors Promoters CRE, SRE Gene expressionDNABP nucleus ER biological response
  17. 17. CICR Signaling and Detection λex: 340 and 380 nm λem: 510 nm 1 https://www.lifetechnologies.com/order/catalog/product/F1201 2 Herzog et al. PNAS 1992, 89 (13), 5794-5798. O O N O N O N O O OO O O O O COO- Ca2+ O N O O O O O O N O O O O O O O O O N O O O O O O O O CytosolSES Fura-2AM Fura-2 bound to Ca2+
  18. 18. Y2 Receptor-Stimulated CICR 1 vs. 2 vs. 3 Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122. PYY3-36 1 2 3 Compound EC50 (nM) PYY3-36 16 1 72 2 27 3 127
  19. 19. Y1 Receptor-Stimulated CICR PYY1-36 PYY3-36 2 Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122. Compound EC50 (nM) PYY1-36 10 PYY3-36 620 2 2200
  20. 20. Y1 vs. Y2 Receptor Nygaard et al. Biochemistry 2006, 45 (27), 8350-8357. PYY1-36 PYY3-36 PYY1-36 PYY3-36
  21. 21. Synthesis of Null Conjugate B12-PYYC36 (4) SPDP: 3-(2-pyridylthio)propionic acid N-hydroxysuccinimide ester Doyle et al. ChemMedChem 2014, 9 (6), 1244-1251.
  22. 22. Y2-Receptor Stimulated CICR PYY3-36 & 2 vs. PYYC36 & 4 1 Beck-Sickinger et al. J. Pept. Sci. 2000, 6 (3), 97-122. 2 Pederson et al. J. Pept. Sci. 2009, 15 (11), 753-759. 3 Beck-Sickinger et al. Eur. J. Biochem. 1994, 225 (3), 947-958. PYY3-36 2 PYYC36 4 Compound EC50 (nM) PYY3-36 16 2 27 PYYC36 762 4 1809
  23. 23. Aim 3: In vivo feeding studies (sc) with PYY3-36, 2, and 4 in rats* Goals 1. Optimize dosing in lean (Sprague Dawley) male rats 2. Acclimate rats to experimental schedule 3. Pharmacodynamic (PD) analysis 4. Pharmacokinetic (PK) analysis 5. Elucidate mechanism of action 6. Repeat sc studies in obese (Zucker) male rats *All animal studies performed in collaboration with Dr. Christian Roth and Clinton Elfers at Seattle’s Children’s Research Institute in Seattle, WA
  24. 24. Dose Escalation Study with 2 Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
  25. 25. Thermal/Solution Stability of 2 *All samples ran at 300 nM Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
  26. 26. Implanting Microinfusion Pumps
  27. 27. Dosing Schedule Baseline PYY3-36 Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749. Baseline 2 Baseline PYY3-36
  28. 28. Food Intake Trends 4 2 PYY3-36 4 2 PYY3-36 * P < 0.05 Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749.
  29. 29. Food Intake Trends 23.7% reduction in food intake due to treatment with 2 and a 13.2% reduction in food intake due to treatment with PYY3-36 4 2 PYY3-36 4 2 PYY3-36 10 day treatment • 2 (n = 6) • PYY3-36 (n = 4) • 4 (n = 4) 5 day treatment • 2 (n = 9) • PYY3-36 (n = 8) • 4 (n = 5) * P < 0.05 ** P < 0.01 *** P < 0.001 1 Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749. 2 Reidelberger et al. Am. J. Physiol.: Regul. Integr. Comp. Physiol. 2006, 290 (2), R298-305. 3 Pittner et al. Int. J. Obes. Relat. Metab. Disord. 2004, 28 (8), 963-971.
  30. 30. * P < 0.05 ** P < 0.01 Body Weight Gain 1 Henry et al. Endocrinology 2015, 156 (5), DOI: en.2014-1825. 2 Reidelberger et al. Am. J. Physiol.: Regul. Integr. Comp. Physiol. 2006, 290 (2), R298-305. 3 Pittner et al. Int. J. Obes. Relat. Metab. Disord. 2004, 28 (8), 963-971. 4 2 PYY3-36
  31. 31. Pulses of Drugs and Time of Action Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749. PYY3-36 B12-PYY3-36PYY3-36 B12-PYY3-36 PYY3-36 B12-PYY3-36 PYY3-36 B12-PYY3-36PYY3-36 2 PYY3-36 2 PYY3-36 2 PYY3-36 2 * P < 0.05 2 PYY3-36 4
  32. 32. In Vivo Uptake Studies Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749. ** * ** 10 nmol/kg 6 10 nmol/kg PYY3-36 10 nmol/kg 2 (n = 4) 10 nmol/kg PYY3-36 (n = 3) Drug AUC0-∞ (pg/h/ml) Cmax (pg/mL) t1/2 (h) VD/F (L/kg) CL/F (mL/min/kg) PYY3-36 3843 ± 1125 1680 ± 243 0.82 ± 0.16 12.8 ± 1.5 188.6 ± 65.6 2 7130 ± 2050 2520 ± 257 1.34 ± 0.28 15.0 ± 1.5 133 ± 32 Tmax = 1 h * P < 0.05 ** P < 0.01
  33. 33. PYY3-36: Mechanisms of Action BRAIN GUT BLOOD Vagal nerve carries sensory information from the Y2 receptors in the gut to solitary tract nucleus (NTS)2 Circumventricular organs3 1 Nonaka et al. J Pharmacol. Exp. Ther. 2003, 306 (3), 948-953. 2 Abbott et al. Brain Res. 2005, 1044 (1), 127-131. 3 Koda et al. Endocrinology, 2005, 146 (5), 2369-2375. CENTRAL PERIPHERAL PYY3-36 crosses BBB and activates Y2 receptors in the arcuate nucleus (ARC)1
  34. 34. C-Fos Immunohistochemistry PYY3-36 2 4 Saline Y2 Receptor Activation ! !Y2 Receptor Activation Vagus Nerve 1 Doyle R.P. et al. Endocrinology 2015, 156 (5), 1739-1749. 2 Blevins et al. Peptides 2008, 29 (1), 112-119. 3 Schwartz et al. Nature 2000, 404 (6778), 661-671. * P < 0.05 2 (n = 9) PYY3-36 (n = 8) 4 (n = 5)
  35. 35. Design of NOTA-2 Doyle R.P. et al. unpublished data.
  36. 36. 64Cu-NOTA-2 PET Scan Administered Dose recovered in brain for 2 vs. PYY3-36. (2-tailed p=0.08). 15 μCi injected dose 64Cu-labeled conjugate by iv. 3 h PET scan of Sprague Dawley rats (n = 3) Doyle R.P. et al. unpublished data.
  37. 37. Zucker Rats: FI Trends Average FoodIntake(g/day) Baseline 4d Treatment 0 10 20 30 40 B12-PYY3-36 PYY3-36 * * 2 PYY3-36 * P < 0.05 2 (n = 3) PYY3-36 (n = 5) Doyle R.P. et al. unpublished data.
  38. 38. Zucker Rats: BW Trends BodyWeight(g) Day 0 Day 10 Day 20 Day 30 750 800 850 900 950 1000 B12-PYY3-36 PYY3-36 Baseline Treatment Compensation 6 PYY3-36 2 PYY3-36 * P < 0.05 DBodyWeight(g) 4 day 10 day -30 -20 -10 0 B12-PYY3-36 PYY3-36 * * *p<0.05 compared to pretreatment 2 PYY3-36 Average FoodIntake(g/ Baseline 4d Treatment 0 10 20 30 B12-PYY3-36 PYY3-36 * * 2 PYY3-36 Doyle R.P. et al. unpublished data.
  39. 39. Conclusions and Summary ** * ** 10 nmol/kg 6 10 nmol/kg PYY3-36 10 nmol/kg 2 10 nmol/kg PYY3-36 4 2 PYY3-36 2 PYY3-36 4 Average FoodIntake(g/day) Baseline 4d Treatment 0 10 20 30 40 B12-PYY3-36 PYY3-36 * * DBodyWeight(g) 4 day 10 day -30 -20 -10 0 B12-PYY3-36 PYY3-36 * * *p<0.05 compared to pretreatment
  40. 40. Future Work: SUPER PYY! GLP1-R agonism Y2-R biased agonism Doyle R.P. et al. unpublished data; Patent Filed Sept. 2015
  41. 41. Thank you to our event sponsor Innovative drug infusion technology for laboratory animals.
  42. 42. Dr. Robert Doyle rpdoyle@syr.edu Thank You! For additional information on iPrecio infusion pumps and Innovative drug infusion technologies for laboratory animals please visit: http://www.iprecio.com/

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