CEHPALOSPORINS.pptx By Harshvardhan Dev Bhoomi Uttarakhand University
Pancoronary therapy with ipdd
1. Pancoronary Therapy withPancoronary Therapy with
Intrapericardial Drug DeliveryIntrapericardial Drug Delivery
Sergio Waxman, M.D.
Lahey Clinic Medical Center
Tufts University School of Medicine
4. Treatment planTreatment plan
Stenting of 2 “tightest” lesions in RCAStenting of 2 “tightest” lesions in RCA
Aggressive medical therapy: statins,Aggressive medical therapy: statins,
aspirin, clopidogrel, smoking cessationaspirin, clopidogrel, smoking cessation
Pre Post
5. But… what about those lesions leftBut… what about those lesions left
behind?behind?
2.5 to 3.5 non-culprit TCFA’s per MI patient2.5 to 3.5 non-culprit TCFA’s per MI patient
20% risk of thrombosis/lesion/2 years20% risk of thrombosis/lesion/2 years
Only 1 in 3 thrombotic lesions will lead to ACSOnly 1 in 3 thrombotic lesions will lead to ACS
20% chance of ACS within 2 years20% chance of ACS within 2 years
40% risk reduction with statins, 50% with40% risk reduction with statins, 50% with
combined medRx, still 12% risk of ACS within 2combined medRx, still 12% risk of ACS within 2
yearsyears
Risk of a DES in focal lesion: 0.5% SAT, 3%Risk of a DES in focal lesion: 0.5% SAT, 3%
restenosisrestenosis
7. Rationale for IP Drug Delivery forRationale for IP Drug Delivery for
Local Cardiac TherapyLocal Cardiac Therapy
Natural barrier action ofNatural barrier action of
the pericardiumthe pericardium
Possible regulatory role inPossible regulatory role in
myocardial and coronarymyocardial and coronary
tissuetissue
Limited or delayedLimited or delayed
absorption into systemicabsorption into systemic
circulationcirculation
Increased residence timeIncreased residence time
in pericardial space andin pericardial space and
exposure to target tissue(s)exposure to target tissue(s)
8. Rationale for IP DeliveryRationale for IP Delivery
Therefore, it should be possible to:Therefore, it should be possible to:
Deliver small dosesDeliver small doses
Obtain high local tissue concentrationsObtain high local tissue concentrations
Limit side effectsLimit side effects
Target tissues
9. Pericardial FluidPericardial Fluid
May Be More than Just An Innocent BystanderMay Be More than Just An Innocent Bystander
PF Serum P
Na+
, mmol/L 139±1 138 ±0 NS
K+
, mmol/L 4.1±0.1 3.9±0.2 .02
Glucose, mmol/L 5.4±0.2 6.8 ±0.2 .001
Osmolarity, mOsm/L 250±4 255 ±3 .001
Protein, g/L 26±2 65 ±2 .001
FGF2, g/L 565 ±120 pg/mL 18±2 pg/mL .001
TGF-ß, g/L 1.1±0.2 ng/mL 13.2 ±2.5 ng/mL .001
Endothelin-1, pg/mL 3.4 ±0.4 4.4±0.4 NS
Angiotensin II, pg/mL 58±9 147 ±36 .04
ANF, pg/mL 137±38 69 ±24 .02
Corda S et al, Circ Res 1997;81:679-87
10. Elevated bFGF in Pericardial Fluid ofElevated bFGF in Pericardial Fluid of
Patients with Unstable AnginaPatients with Unstable Angina
Fujita et al, Circulation 1996;94:610-13
11. Delayed Clearance of RadiolabeledDelayed Clearance of Radiolabeled
Agents from Pericardial Space: SizeAgents from Pericardial Space: Size
MattersMatters
MW 479 Da
MW 74 kDa
Baek SH et al. Circulation 2002;105:2779-84
12. Residual Radioactivity FollowingResidual Radioactivity Following
Delivery ofDelivery of 131131
I-labeled NONO-albuminI-labeled NONO-albumin
T 1/2=2.5-3.9 hrs
T 1/2=22.2 hrs
Stoll HP et al. Clinical Cardiology 1999;22(Suppl I):10-16
13. Persistent coronary vasodilatation induced byPersistent coronary vasodilatation induced by
intrapericardial nitroglycerinintrapericardial nitroglycerin
Waxman S et al, JACC 1999;33:2073-7
14. Higher Concentrations AchievedHigher Concentrations Achieved
with Pericardial vs IV Deliverywith Pericardial vs IV Delivery
Hermans et al. JPET 2002;301:672-78
15. Fractional intramuralFractional intramural deliverydelivery andand retentionretention inin
the coronary artery ofthe coronary artery of 125125
I labeled agentsI labeled agents
Stoll HP et al. Clinical Cardiology 1999;22(Suppl I):10-16
Uniform Concentration Persistent Concentration
16. Inhibition of neointima formation withInhibition of neointima formation with
intrapericardial paclitaxel after balloon overstretchintrapericardial paclitaxel after balloon overstretch
Control
Paclitaxel, 10 mg
Paclitaxel, 50 mg
Hou et al, Circulation 2000;102:1575
17. VEGF levels following intrapericardialVEGF levels following intrapericardial
adenoviral-mediated gene transferadenoviral-mediated gene transfer
(AdCMV.VEGF, AdRSV.β-gal) in a canine model(AdCMV.VEGF, AdRSV.β-gal) in a canine model
of chronic ischemiaof chronic ischemia
Lazarous et al, Cardiovascular Research 1999;44:299
18. Pericardially delivered EPC Migrate toPericardially delivered EPC Migrate to
Areas of Ischemic MyocardiumAreas of Ischemic Myocardium
0
100
200
300
400
500
600
AW AS IP Lung Liver
7d +EPC
7d control
21d +EPC
Location of Cells
CellDensity(cells/mm2
)
Saltzman AJ, Karas R, WaxmanS, et al. Circulation Suppl 2003
19. Intrapericardial drug delivery:Intrapericardial drug delivery:
Potential pancoronary therapeutic applicationsPotential pancoronary therapeutic applications
Modulation of coronary response to injuryModulation of coronary response to injury
RestenosisRestenosis
Plaque stabilization/regression/Vulnerable PlaquePlaque stabilization/regression/Vulnerable Plaque
20. How do we get there?How do we get there?
Direct surgical approachDirect surgical approach
““Outside” inOutside” in
SubxiphoidSubxiphoid
PerducerPerducer
““Inside” outInside” out
TransatrialTransatrial
TransventricularTransventricular
21. PerduCer™ device for intrapericardialPerduCer™ device for intrapericardial
accessaccess
Courtesy of Comedicus Inc.
22. Transventricular pericardial access usingTransventricular pericardial access using
a helical tipped cathetera helical tipped catheter
March, KL. Clinical Cardiol 1999
23. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
Verrier, Waxman, et al, Circulation 1998;98:2331;
Waxman et al, Cath Cardiovasc Interv 2000;49:472
24. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
Guide positioning inGuide positioning in
right atrial appendage.right atrial appendage.
Puncture of appendagePuncture of appendage
with 2 wire systemwith 2 wire system
25. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
Advancement of infusionAdvancement of infusion
catheter into pericardialcatheter into pericardial
spacespace
Confirmation:Confirmation:
fluoroscopy andfluoroscopy and
pericardial fluidpericardial fluid
aspirationaspiration
27. Use of polymers in the pericardial space for drugUse of polymers in the pericardial space for drug
deliverydelivery
Waxman et al, Circulation 2001;104 (Suppl):II-729
28. ConclusionsConclusions
The pericardial space may be an appropriate platformThe pericardial space may be an appropriate platform
for local pancoronary therapy for VP:for local pancoronary therapy for VP:
Localized effectsLocalized effects
Small dosesSmall doses
High efficiencyHigh efficiency
Mounting evidence suggests that pharmacologicalMounting evidence suggests that pharmacological
and biological agents may be delivered via thisand biological agents may be delivered via this
approach to exert a local coronary vascular effect.approach to exert a local coronary vascular effect.
29. Intrapericardial DeliveryIntrapericardial Delivery
ChallengesChallenges
What agents?What agents?
How practical is it? How do we get there?How practical is it? How do we get there?
Possible need for repeated dosesPossible need for repeated doses
Penetrability of therapeutic agent in tissuesPenetrability of therapeutic agent in tissues
Is there a need for “booster treatment”?Is there a need for “booster treatment”?
Patient selectionPatient selection
30. AcknowledgementsAcknowledgements
Center for TranslationalCenter for Translational
Cardiovascular Research, Tufts-Cardiovascular Research, Tufts-
NEMCNEMC
Sung Choi, MDSung Choi, MD
Alexandra DabreoAlexandra Dabreo
Fumiyuki Ishibashi, MDFumiyuki Ishibashi, MD
Adam Saltzman, MDAdam Saltzman, MD
Eric WeissEric Weiss
Molecular Cardiology ResearchMolecular Cardiology Research
Institute, Tufts-NEMCInstitute, Tufts-NEMC
Wendy BaurWendy Baur
Flore CelestinFlore Celestin
Richard Karas, MDRichard Karas, MD
Beth Israel DeaconessBeth Israel Deaconess
Medical CenterMedical Center
Richard Verrier, PhDRichard Verrier, PhD
31. Distribution ofDistribution of 125125
I bFGF after 5 differentI bFGF after 5 different
routes of deliveryroutes of delivery
Lazarous DF et al. Cardiovascular Research 1997;36:78-85
32. Luciferase expression at 3 days following geneLuciferase expression at 3 days following gene
transfer with intrapericardial delivery, Av1Lu.transfer with intrapericardial delivery, Av1Lu.
March KL et al, Clinical Cardiol 1999;22 (Suppl I):23-29