Nimodipine

Authors:

Joe M. Das, Patrick M. Zito

Findings:

Nimodipine significantly increased the odds of vocal fold motion recovery (OR 13.73, P < .01) and facial motion recovery (OR 2.78, P = .02) after injury compared to controls. Overall, nimodipine-treated patients had significantly higher odds of recovering vocal fold or facial motion (OR 6.09, P < .01). Existing evidence supports a positive effect.

Participants:

Human participants with recurrent laryngeal nerve or facial nerve injury (N=110 nimodipine, N=556 controls in meta-analysis).

Study Quality Assessment:

Systematic review and meta-analysis following preferred reporting items for systematic reviews and meta analyses (PRISMA) guidelines. Included 9 human studies (5 used in meta-analysis, N=110 participants, N=556 controls). Acknowledges need for future randomized clinical trials.

All Effects:

Findings:

Evidence from reviewed RCTs indicates nimodipine reduces the risk for Delayed Cerebral Ischemia (DCI)-related death or vegetative state (pooled RR: 0.62 in three trials). Fixed-dose regimens were associated with a reduction in all-cause infarct and death independent of DCI (pooled RR: 0.60). Further studies assessing benefits beyond death/vegetative state and using individualized dosing are needed.

Participants:

Patients with aneurysmal subarachnoid hemorrhage (Data from reviewed Randomized Control Trials, including three trials with a total of 349 patients).

Dosage:

Compared fixed versus weight-based nimodipine dosing regimens. Found fixed-dose regimens favoured reduction in all-cause infarct and death. Original studies applied variable dosing regimens.

Study Quality Assessment:

Scoping review based on PRISMA guidelines. Evaluated evidence from Randomized Control Trials (RCTs), selecting eight RCTs. Outcome measure for selection: neurological benefit. Compared fixed versus weight-based dosing. Limitations of original studies reviewed were noted (not reflecting current practice, dichotomised outcomes, variable dosing, including non-DCI causes of poor outcome). A declaration of no competing financial interests or personal relationships was included.

All Effects:

Findings:

This network meta-analysis found no statistically significant difference between intravenous and enteral nimodipine administration routes regarding case fatality, incidence of delayed cerebral ischemia (DCI), delayed ischemic neurologic deficit (DIND), or poor outcomes at 3 months in patients with SAH. Both administration routes were significantly more effective than placebo for these outcomes. The study concludes that enteral and intravenous nimodipine may have comparable effectiveness, but further high-quality RCTs are needed to confirm this and assess differences in specific patient subsets.

Participants:

Patients with subarachnoid hemorrhage (SAH). Included studies involved patients with varying clinical grades (Hunt and Hess I-V, World Federation of Neurosurgeons I-V).

Dosage:

Included studies used various doses: Enteral nimodipine ranged from 28 mg/day to 540 mg/day (e.g., 3 mg/kg divided in 6 daily doses, 360 mg/d, 540 mg/d). Intravenous nimodipine doses included 48 mg/day and 0.5 μg/kg/min. Duration of treatment ranged from 7 to 21 days.

Study Quality Assessment:

Systematic review and network meta-analysis (NMA) of nine randomized controlled trials (RCTs). Followed PRISMA guidelines and PRISMA NMA Extension statement. Searched Pubmed, Embase, Web of Science, and Cochrane databases. Quality assessment performed using Cochrane Handbook, revealing varying risks of bias across included studies (e.g., high risk for sequence generation in 5/9 studies, unclear risk for allocation concealment in 6/9). Statistical methods included Bayesian NMA, random-effects model, node-splitting for consistency checks, and SUCRA for ranking. Limitations acknowledged include: degree of bias in included studies, less standardized dose/duration for IV nimodipine compared to enteral, search limited to 4 databases, included studies spanned 30 years (potential impact from protocol/definition changes), results represent average outcomes not stratified by SAH severity.

All Effects:

Authors:

Caroline F Zink

Findings:

A single 60 mg dose of nimodipine significantly decreased frontal and parietal cortical activity during an N-back working memory task in healthy men, without changing task performance, suggesting improved cortical efficiency. This effect was concentration-dependent and more pronounced in carriers of the CACNA1C rs1006737 risk allele (A). Nimodipine did not significantly affect brain activation during other cognitive/emotional tasks or alter mood states.

Participants:

Healthy, non-smoking, Caucasian, right-handed men aged 18–35 years old (mean age 25.8 ± 3.68). Thirty subjects completed the study, with 28 included in the N-back fMRI analyses. Participants were prospectively genotyped for rs1006737 (14 GG, 4 GA, 10 AA risk-associated genotype among the 28 analyzed).

Dosage:

Single 60 mg dose of oral nimodipine solution (20 mL of Nymalize®).

Study Quality Assessment:

Double-blind, randomized, cross-over, placebo-controlled pharmacoMRI study (N=30 completed, N=28 analyzed for N-back fMRI). Used fMRI (BOLD signal), N-back task, genotyping (rs1006737), plasma nimodipine concentration measurement (LC-MS), statistical analysis (SPM12, paired t-test, linear regression, pFWE < 0.05 threshold). Funding source mentioned (The Lieber Institute for Brain Development, drug/placebo donated by Arbor Pharmaceuticals, LLC). Limitations acknowledged: MRI system upgraded mid-study, N-back task may lack behavioral sensitivity in healthy subjects performing at ceiling.

All Effects:

Authors:

Andrew P Carlson, Daniel Hänggi

Findings:

Nimodipine, an L-type calcium channel blocker, is approved for improving outcomes in aneurysmal subarachnoid hemorrhage (aSAH), likely acting via complex mechanisms including mitigating spreading depolarization (SD), not just vasodilation. While trials in ischemic stroke and traumatic brain injury (TBI) were largely negative, possibly due to hypotension side effects, and migraine use faded despite some positive data, newer understanding of SD pathophysiology and local delivery methods (like EG-1962) offer potential for reappraisal. Local delivery aims to enhance efficacy and reduce hypotension, but a recent Phase 3 trial (NEWTON-2) for aSAH was halted early, requiring further analysis.

Participants:

The review discusses studies involving various participants: Patients with aneurysmal subarachnoid hemorrhage (aSAH) across different severity grades (Hunt and Hess grades I-IV), ischemic stroke, traumatic brain injury (TBI, including traumatic SAH), migraine (common and classic, pediatric), post-cardiac arrest/surgery, elderly individuals with cognitive decline (including Alzheimer's, vascular dementia), and other conditions like motor neuron disease, epilepsy, vertigo. Healthy human subjects were also studied. Animal models included rats, dogs, rabbits, cats, and beagles. In vitro studies used neuronal, astrocyte, and microglia cultures, and brain slices. Specific sample sizes (N=X) are mentioned for several individual trials discussed.

Dosage:

Standard oral nimodipine regimen for aSAH is implied but not detailed; IV formulation used in Europe. Specific doses mentioned include: IV 2 mg/h for 7 days (TBI trial); intra-arterial infusion 50 mL/hour (aSAH pilot); sustained-release intraventricular EG-1962 tested up to 800 mg MTD, with 600 mg used in Phase 3 (aSAH); 12 mg dose mentioned in a stroke subgroup. Higher doses linked to hypotension (plasma >= 70 nmol/L) and potentially worse outcomes in stroke. EG-1962 provides sustained release over 21 days.

Study Quality Assessment:

The review discusses numerous studies, including randomized controlled trials (RCTs, often double-blind, placebo-controlled, multicenter), systematic reviews (Cochrane), meta-analyses, phase 1-3 trials, and preclinical studies (animal models, in vitro). Methodologies mentioned include PET, SPECT, angiography, CSF/plasma concentration analysis, and specific clinical scales (GOSE, Hunt & Hess). Limitations noted include potential issues with early trial quality, risk of hypotension confounding results (especially in stroke/TBI), heterogeneity of conditions like TBI, challenges with drug delivery (invasiveness, limitations of pellets), early halting of a Phase 3 trial (NEWTON-2) for futility despite subgroup signals, and potential funding bias acknowledged (Edge Therapeutics funding, author conflicts).

All Effects: