1. Local Drug Delivery for Renal Denervation
Kirk P. Seward, PhD
President and CTO
Mercator MedSystems

2. Disclosures Mercator MedSystems, Inc.
Employee
Shareholder
Guanethidine is not approved for localized renal denervation

3. 1.0 mm
media
adventitia
Target: renal
nerves

4. FDA 510(k) Microneedle: 130-180 micron diameter, 0.9-1.5 mm length
2-8 mm treatment diameters

7. What to Deliver? Toxins or curares (botox, tetrodotoxin)
Short acting or highly toxic to CNS
Solvents (ETOH)
Not specific to nerves
Anesthetics (lidocaine, bupivicaine)
Only offer transient block
Sympatholytics

8. Localized Guanethidine Sympathectomy Innovating a well-known drug
Approved in 1960 for treatment of moderate to severe hypertension
Drawn specifically into sympathetic nerves by norepinephrine uptake pump
Low dose: interferes with excitatory vesicular release from sympathetic terminals
High dose: causes localized sympathectomy
Inhibits mitochondrial respiration*
Induces immune response*
Ideal local agent due to specificity for postganglionic denervation N H NH
NH2
Phamacokinetics of guanethidine
Renal clearance 56±14 ml/min
t1/2i = 1.5 days
t1/2ii = days
*Manning P. et al, J Neurosci 1983;3(4):
Europ J Clin Pharmacol. 1979;15:

9. Renal Adventitial Guanethidine Delivery Safe and Effective Denervation in Preclinical Studies
Guanethidine specificity in the adventitia:
Control: normal renal adventitial nerve fascicles
24 hours after guanethidine: injured nerve fascicles
Localized tissue effect – no spread to adjacent nerve structures
No histological evidence of renal artery damage
Safety:
Chronic evidence of guanethidine denervation:
58% reduction of kidney norepinephrine (NE) at 28d
Nerve atrophy at 60d

10. Adventitial Guanethidine Pharmacokinetics

11. Enhanced Targeting: pH Effect
LC50 levels, 48-hour guanethidine exposure

12. Desirable vs. Unnecessary Fibrosis
ARDIAN/MEDTRONIC
MEDIAL
Rippy MK, et al. Clin Res Cardiol 2011;100(12):
Accad M. LINC2012.
MAYA/COVIDIEN
ADVENTITITAL/
PERINEURAL
MERCATOR

13. Desirable vs. Unnecessary Fibrosis
Normal Nerves
Fibrosed/Atrophied Nerves
30 days
60 days

14. Can We Improve on Spasm and Pain?
Energy-based denervation
Pharmaceutical denervation
Intense Procedural Pain
No Anticipated Pain
Could adventitial lidocaine reduce procedural pain?
Common Vasospasm
No Vasospasm

15. Future Desires and Directions
 Pain, morphine use
 Injury
 Responder rate
 Cath lab time
- procedure and f/u vasospasm
 Catheter size to enable radial approach
 Inclusion criteria – RAS, CKD