Therapeutics

Nimodipine

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Overview

Name: Nimodipine
Synonyms: Nimotop
Chemical Name: 3-(2-methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Therapy Type: Small Molecule (timeline)
Target Type: Metals
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Discontinued)
Company: Bayer
Approved for: Subarachnoid hemorrhage

Background

Nimodipine is a calcium channel blocker. It is prescribed to prevent vasospasm and possible subsequent stroke in people who have suffered a hemorrhage in the subarachnoid space, the compartment surrounding the brain.

The rationale in evaluating nimodipine capsules in frontotemporal dementia is that it is believed to increase levels of progranulin (see 2012 New York Times story). Plasma and CSF concentrations of this protein are reduced in carriers of pathogenic progranulin mutations, which generally cause progranulin haploinsufficiency and constitute a major genetic cause of FTD (Finch et al., 2009).

Findings

In 2013 and 2014, a pilot trial at the University of California, San Francisco, evaluated nimodipine in eight symptomatic and asymptomatic carriers of loss-of-function mutations in the gene for progranulin. Participants first took escalating doses of nimodipine for a period of four weeks, then the maximum tolerated dose for another four weeks, and then underwent one week of tapering off. This open-label trial aimed primarily to determine the maximum tolerated dose of nimodipine in this patient population as preparation for further efficacy trials. Secondary outcome measures of the trial included plasma progranulin levels measured throughout the trial, CSF progranulin levels measured twice, plasma and CSF cytokine levels, and MRI scan.

The trial was completed in May 2016. As presented at the International Conference on Frontotemporal Dementias, nimodipine was well-tolerated, but did not change progranulin concentrations or alter any of the secondary outcomes (Sep 2016 conference news). Results were subsequently published in a peer-reviewed journal (Sha et al., 2017).

For details, see clinical trials.gov.

Last Updated: 11 Sep 2020

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References

News Citations

  1. First Round of FTD Therapeutics Fell Short, But Many More Are Up and Running

Alzpedia Citations

  1. Progranulin

Paper Citations

  1. Sha SJ, Miller ZA, Min SW, Zhou Y, Brown J, Mitic LL, Karydas A, Koestler M, Tsai R, Corbetta-Rastelli C, Lin S, Hare E, Fields S, Fleischmann KE, Powers R, Fitch R, Martens LH, Shamloo M, Fagan AM, Farese RV Jr, Pearlman R, Seeley W, Miller BL, Gan L, Boxer AL. An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimers Dement (N Y). 2017 Nov;3(4):507-512. Epub 2017 Sep 12 PubMed.
  2. Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain. 2009 Mar;132(Pt 3):583-91. PubMed.

External Citations

  1. clinical trials.gov
  2. 2012 New York Times story

Further Reading