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Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease


Does Physiologic Phenotype Predict the Pattern of Parkinson’s Disease Pathology? While isradipine might be effective in protecting SNc DA neurons, will it be effective in other regions affected by PD? There are a number of regions of the brain that have cell loss paralleling that of the SNc.7 Although the available data set is fragmented, neurons in the dorsal motor nucleus of the vagus (DMV), locus ceruleus (LC), raphe nuclei (RN), pedunculopontine nucleus (PPN), lateral hypothalamus (LH), tuberomammillary nucleus, basal forebrain (BF), and olfactory bulb all exhibit signs of pathology and all have a physiologic phenotype resembling that of SNc DA neurons. DMV cholinergic neurons, which are thought to be among the earliest neurons with α-synuclein in PD, are spontaneously active;33


this activity is autonomously generated and


engages L-type calcium channels (unpublished observations). Serotonergic neurons in the RN have broad spikes and are calcium-dependent autonomous pacemakers.34


This is also true of PPN cholinergic neurons.35


Tuberomammillary neurons are spontaneously active and engage L-type Ca2+ channels.36


autonomous pacemakers.37


Perhaps the neurons most affected in PD, other than SNc DA neurons, are LC noradrenergic neurons.7


Like SNc DA neurons, they are


Moreover, these neurons display all the signs of mitochondrial oxidant stress found in SNc DA neurons and this stress is significantly alleviated by isradipine. Taken together, these studies make a compelling case that the DHP class of agents should be broadly effective in slowing the progression of PD.


Epidemiologic Studies


Recent epidemiologic data also supports the potential neuroprotective effect of DHPs in PD. Two studies demonstrated reduced risk of development of PD in subjects treated with calcium channel blockers (CCBs) compared to other antihypertensive agents.39,40


The most recent


study assessed the risk of the new diagnosis of PD in a cohort of 1,931 patients with new diagnosis of PD versus 9,651 matched controls. The study demonstrated a 27 % risk reduction (OR=0.73) of a new diagnosis of PD in subjects treated with centrally acting DHP compounds compared to other CCBs or other antihypertensive agents. That study provides strong supporting evidence of channel specific selectivity of the potential neuroprotective effect of CCBs restricted to DHP compounds. The study also provides indirect evidence of sufficient CNS penetration of the subset of DHPs as the risk reduction was seen only with the centrally acting DHPs and not observed with amlodipine that has low CNS penetration.


Isradipine


Currently, there are no Cav1.3 channel selective DHPs. Isradipine is the most potent DHP at these channels and is FDA approved for treatment


of hypertension since 1990.41 Isradipine is available in immediate


(IR) and controlled release (CR) preparation in 5–20 mg dose range. Isradipine is rapidly and almost completely (90–95 %) adsorbed following oral administration but undergoes extensive first pass metabolism, resulting in bioavailability of 15–24 %. Peak serum levels


autonomous pacemakers (with broad spikes) that engage L-type calcium channels.38


DA neurons in the olfactory bulb are calcium-dependent,


Isradipine belongs to the group of lipophilic DHPs that have good bioavailability in non-human primates with brain to serum concentration ratios significantly above one.42


Isradipine is among the


more lipophilic DHPs, enhancing its brain bioavailability. Recently published epidemiologic data showing a reduced incidence of PD in patients treated with centrally bioavailable DHPs also strongly supports good CNS penetration of DHPs.40


Preliminary Human Data


We have conducted an open-label dose escalation safety and tolerability study of isradipine in patients with early PD. The study demonstrated dose-dependent tolerability of isradipine CR: 94 % for a 5 mg dose; 87 % for a 10 mg dose; 68 % for a 15 mg dose; and 52 % for a 20 mg dose.43 Isardipine had no significant effect on blood pressure or PD motor disability. The two most common reasons for dose reduction were leg edema (seven) and dizziness (three). There was no difference in isradipine tolerability between subjects with and without dopaminergic treatment. That study supports good tolerability of isradipine CR at daily doses up to 10 mg in subjects with early PD.


A pilot Phase II double-blind, placebo-controlled, tolerability- and dosage-finding study of isradipine CR as a disease modifying agent in patients with early PD (STEADY-PD) supported by the Michael J Fox Foundation is ongoing. The objective of the study is to establish safety and tolerability of isradipine CR across the FDA-approved dosing range (5–20 mg) in a larger cohort of patients with early PD and to evaluate the comparative efficacy of three doses of isradipine CR, provided that they are tolerable. The study recruited subjects with early PD not requiring dopaminergic therapy (stable dose of amantadine, anticholinergics, and monoamine oxidase (MAO-B) inhibitors are allowed). The study is designed as a multicenter 52 weeks’ duration, randomized, four-arm double-blind parallel group trial, with 100 subjects randomized to 5, 10, or 20 mg of isradipine CR or matching placebo daily. The dosage that is tolerable and demonstrates preliminary efficacy will be used in the future pivotal efficacy study.44


Tolerability of each active dosage will be compared with the tolerability of placebo. Provided that the dose is tolerable, the choice for the dose selection will be based on efficacy defined as the change in total UPDRS score between the baseline visit and month 12 or the time of sufficient disability to require dopaminergic therapy, whichever occurs first. Comparison will be made between three active treatment arms. The dosage that demonstrates the greatest efficacy will be used in the proposed pivotal study. The study has successfully completed recruitment, with the final data analysis expected to be available in the next six months.


Conclusion


There is solid scientific rationale, preclinical, and epidemiologic data to support the potential benefit of isradipine as a disease modifying agent in early PD. Results of the ongoing Phase II study will be available shortly and will inform the design of the future pivotal efficacy trial. n


occur in about 1.5 hours for the IR preparation and 8–10 hours for the CR preparation. Animal studies have demonstrated a neuroprotective effect of isradipine in an intrastriatal 6-OHDA model at the serum concentrations achievable within the dose range approved for human use.32


US NEUROLOGY


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