Iontophoresis: Quantitative drug delivery

Evaluation of Vascular Reactivity in Alzheimer’s Disease via Iontophoresis of Vasoactive Compounds

Thomas Budinger, M.D., Ph.D.Jonathan Maltz, Ph.D.William Jagust, M.D.Jamie Eberling, Ph.D.Bruce Miller, M.D.

Hypothesis

Altered dilatory response of brain vasculatureis an important factor in the development of AD.This altered response is systemic and affects theperipheral circulation as well as the brain.

Hypothesis suggested by

1. Increased incidence of AD in patients with cardiovascular disease.

2. Acetylcholine and nitric oxide (NO) biochemistry issignificantly altered in the AD brain. These agentsare important mediators of vasodilation throughout the body.

Objective

To test the hypothesis that peripheral vasoactivity is altered in AD by evaluating the cutaneous vasodilatory response to vasoactive agents.

We are studying the effects of

- Acetylcholine (ACh)- Methacholine (MCh)- Sodium nitroprusside (SNP)on the cutaneous vasculature of the human forearm.

All elicit vasodilation via the relaxing action of NO on smooth muscle.

ACh, MCh and SNP

ACh: - Relaxes vascular smooth muscle primarily viareceptor stimulation of endothelial cells, which then release NO.

MCh: - Same mode of action as ACh. - More stable. Seems to act directly on smooth

muscle as well as on endothelial cells. - Preferential muscarinic agonist.

SNP: - Releases NO on decomposition. - Acts by directly relaxing smooth muscle.

Iontophoresis: Quantitative drug delivery

Perfusion response to iontophoresis

Laser Doppler imaging: Quantitative measurement of perfusion

Laser Doppler perfusion imaging

Laser Doppler imaging of perfusion response to iontophoresis

Typical response to ACh

Review of previous work

Two studies have investigated cutaneous vasoactivity in AD:

Hörnqvist et al., Gerontology 33(6), 1987

Algotsson et al., Neurobiology of Aging 16(4), 1995

Hörnqvist et al. (1987): Subject selection

12 AD/SDAT patientsAge: 52-84, mean 71Severe dementia, hospitalized

13 controls with various dermatosesAge: 52-82, mean 70

Nicotine and caffeine allowed

Hörnqvist et al.

Hörnqvist et al.: Results

Agent Action AD vs Control

Phenylephrine 1-agonist AD slightly reduced

Isoproterenol 1-agonist AD reduced

p<0.001

Methacholine Muscarinic agonist

Not significant

Algotsson et al. (1995): Subject selection

15 AD patientsMMSE > 2716 Age-matched controlsSubjects lived at home

Algotsson et al.

Algotsson et al.: Results

Agent Action AD vs Control

Sodium nitroprusside

NO donor to smooth muscle

AD reduced

(not significant)

Isoproterenol 1-agonist AD reduced

p < 0.01

Acetylcholine Endothelium dependent vasodilator

AD reduced

p < 0.05

Our study: Subject selection

9 AD patients, age 73 - 88, mean 80.46 on donepezil (Aricept) 5 mg3 on donepezil 10 mgMMSE range: 2 - 28, mean 19.4

8 controls, age 71 - 84, mean 78.6

12 hour fastLipid panel performedSubjects lived at home

Dose

110A for 60 secondsAll solutions: 0.5 – 1 mM

Results

Agent Action AD vs Control

Methacholine Muscarinic agonist

AD increased 42% p < 0.05

Acetylcholine Endothelium dependent vasodilator

AD increased 41% p < 0.16

Sodium nitroprusside

NO donor to smooth muscle

AD increased 35% p < 0.14

Mean response vs. time

Time-integrals of perfusion responses

Donepezil dose dependence

Conclusion

Perfusion response to MCh significantly increased in AD under donepezil therapy. Enhanced response to cholinergic agonists is opposite of what Algotsson et al. observed.

It is impossible to evaluate original hypothesis in this patient population.

Weak negative correlation observed between donepezil dose and response to MCh.

Proposed explanation

AChEis delay the metabolic breakdown of cholinergic agonists in cutaneous tissue.This leads to enhanced and prolonged vasodilation.

Results suggest MCh perfusion studies may be useful in monitoring acetylcholinesterase inhibitor therapy.

Future plans

New UCSF-study, monitoring AChEi-therapy in AD/IVD.

Study of recently diagnosed, untreated subjects.

Acknowledgements

We thank Matthew Darmalingum for assisting in these experiments and in the preparation of this presentation.

This study was performed under NIH grant AG 05890-15 and DOE OBER contract DE-AC03-76SF0098.