Iontophoresis: Quantitative drug delivery

1. Evaluation of Vascular Reactivity in Alzheimer’s Disease via Iontophoresis of Vasoactive CompoundsThomas Budinger, M.D., Ph.D.Jonathan Maltz, Ph.D.William Jagust, M.D.Jamie Eberling, Ph.D.Bruce Miller, M.D.

2. HypothesisAltered 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.

3. Hypothesis suggested by1. 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.

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

5. 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.

6. ACh, MCh and SNPACh: - Relaxes vascular smooth muscle primarily via receptor 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.

7. Iontophoresis: Quantitative drug delivery

8. Perfusion response to iontophoresis

9. Laser Doppler imaging: Quantitative measurement of perfusion

10. Laser Doppler perfusion imaging

11. Laser Doppler imaging of perfusion response to iontophoresis

12. Typical response to ACh

13. Review of previous workTwo studies have investigated cutaneous vasoactivity in AD:Hörnqvist et al., Gerontology 33(6), 1987Algotsson et al., Neurobiology of Aging 16(4), 1995

14. Hörnqvist et al. (1987): Subject selection12 AD/SDAT patientsAge: 52-84, mean 71Severe dementia, hospitalized13 controls with various dermatosesAge: 52-82, mean 70Nicotine and caffeine allowed

15. Hörnqvist et al.

16. Hörnqvist et al.: Results

17. Algotsson et al. (1995): Subject selection15 AD patientsMMSE > 2716 Age-matched controlsSubjects lived at home

18. Algotsson et al.

19. Algotsson et al.: Results

20. Our study: Subject selection9 AD patients, age 73 - 88, mean 80.46 on donepezil (Aricept) 5 mg3 on donepezil 10 mgMMSE range: 2 - 28, mean 19.48 controls, age 71 - 84, mean 78.6 12 hour fastLipid panel performedSubjects lived at home

21. Dose110A for 60 secondsAll solutions: 0.5 – 1 mM

22. Results

23. Mean response vs. time

24. Time-integrals of perfusion responses

25. Donepezil dose dependence

26. ConclusionPerfusion 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.

27. Proposed explanationAChEis 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.

28. Future plansNew UCSF-study, monitoring AChEi-therapy in AD/IVD.Study of recently diagnosed, untreated subjects.AcknowledgementsWe 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.