Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

In vivo phenotypic validation of adenosine receptor-dependent activity of non-adenosine drugs.

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.

The Impact of Nimodipine Administration through Feeding Tube on Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage.

PURPOSE: Delayed cerebral ischemia (DCI) and vasospasm are the main challenges contributing to unfavorable outcomes following aneurysmal subarachnoid hemorrhage. Nimodipine has been shown to decrease the incidence of delayed cerebral ischemia and improve outcomes. In patients who are unable to swallow, nimodipine tablets are crushed and administered through enteral feeding tubes. However, it is not clear whether this may result in reduced clinical effectiveness. The aims of the study were to investigate the impact of nimodipine administration through enteral feeding tubes, in the first 7 days and over the 21-days period on patient outcomes. METHODS: A retrospective chart review of subarachnoid hemorrhage patients admitted at the University of Alberta Hospital, Edmonton, Alberta, Canada was carried out. Logistic regression modelling was utilized to identify predictors of vasospasm and delayed cerebral ischemia. Main outcome measures were angiographic evidence of moderate to severe vasospasm, development of delayed cerebral ischemia and hospital mortality. RESULTS: 85 patients were included. Following adjustment for disease severity, nimodipine administration technique was associated with vasospasm in the first 7 days of patient admission where patients receiving nimodipine via enteral feeding tubes had increased odds of vasospasm compared to those administered it as whole tablets (OR 8.9, 95% CI 1.1-73.1, p value 0.042). When analyzed over the 21-day period, nimodipine administration by feeding tube was associated with increased odds of DCI compared to whole tablets (OR 38.1, 95% CI 1.4-1067.9, p value 0.032). CONCLUSIONS: Our findings suggest that nimodipine administration via enteral feeding tubes may be associated with vasospasm and DCI in subarachnoid hemorrhage patients secondary to reduced exposure. Prospective studies are needed to confirm such association and alternate methods of administration should be explored to ensure patients are getting the benefits of nimodipine.

Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride.

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs-nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)-might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.

Therapeutic effect of piracetam with nimodipine on vascular dementia after cerebral infarction.

This article investigated the clinical effects of piracetam with nimodipine in the treatment of vascular dementia (VD) after cerebral infarction. 98 patients with vascular dementia after cerebral infarction were selected and divided into the control group and the study group according to the treatment method. The control group was treated with nimodipine alone. The study group was treated with piracetam on the basis of this observation, and we test the ADL (life ability score), MoCA(montreal cognitive assessment scale), ADAS-Cog(alzheimer's scale-cognition), MMSE(mental status examination) scores and quality of life scores before and after treatment in the two groups. Before treatment, there were no significant differences in ADL, MoCA, and ADAS-Cog scores between the two groups (P>0.05). After treatment, the ADL, MoCA, and ADAS-Cog scores of the study group were superior to the control group. The difference was statistically significant (P<0.05). There was no significant difference in MMSE scores between the two groups before treatment and 1 month after treatment (P>0.05). The MMSE scores of the study group were better than the control group after 3 months of treatment and half a year after treatment. The difference was statistically significant (P <0.05). Before treatment, there was no significant difference in the quality of life scores between the two groups (P>0.05). After treatment, the quality of life scores was significantly higher than the control group, and the difference was statistically significant (P<0.05). For patients with vascular dementia after cerebral infarction, piracetam combined with nimodipine can improve the cognitive function, improve the quality of life, and have a significant clinical effect.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with an increase of calcium ions within neurons. Inhibiting this increase could protect neurons and might reduce neurological impairment, disability, and handicap after stroke. OBJECTIVES: To assess the effects of calcium antagonists for reducing the risk of death or dependency after acute ischemic stroke. We investigated the influence of different drugs, dosages, routes of administration, time intervals after stroke, and trial design on the outcomes. SEARCH METHODS: The evidence is current to 6 February 2018. We searched the Cochrane Stroke Group Trials Register (6 February 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), MEDLINE Ovid (1950 to 6 February 2018), Embase Ovid (1980 to 6 February 2018), and four Chinese databases (6 February 2018): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese Scientific Periodical Database of VIP information, and Wanfang Data. We also searched the following trials registers: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN registry, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Registry, and we contacted trialists and researchers. SELECTION CRITERIA: Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. We used standard Cochrane methodological procedures. MAIN RESULTS: We included 34 trials involving 7731 participants. All the participants were in the acute stage of ischemic stroke, and their age ranged from 18 to 85 years, with the average age ranging from 52.3 to 74.6 years across different trials. There were more men than women in most trials. Twenty-six trials tested nimodipine, and three trials assessed flunarizine. One trial each used isradipine, nicardipine, PY108-608, fasudil, and lifarizine. More than half of these trials followed participants for at least three months. Calcium antagonists showed no effects on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13; 22 trials; 22 studies; 6684 participants; moderate-quality evidence) or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17; 31 trials; 7483 participants; moderate-quality evidence). Thirteen trials reported adverse events, finding no significant differences between groups. Most trials did not report the allocation process or how they managed missing data, so we considered these at high risk of selection and attrition bias. Most trials reported double-blind methods but did not state who was blinded, and none of the trial protocols were available. AUTHORS' CONCLUSIONS: We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Clinical Trial Protocol: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study Comparing EG-1962 to Standard of Care Oral Nimodipine in Adults with Aneurysmal Subarachnoid Hemorrhage [NEWTON-2 (Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After SubarachNoid Hemorrhage)].

BACKGROUND: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. RESULTS: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine. CONCLUSIONS: The primary endpoint is the proportion of subjects with favorable outcome (6-8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.

Poor Utilization of Nimodipine in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To determine adherence to nimodipine administration in patients admitted with aneurysmal subarachnoid hemorrhage (aSAH). BACKGROUND: Oral nimodipine (60 mg every 4 hours for 21 days) is recommended by the national guidelines for aSAH. A Cochrane systematic review has determined that nimodipine reduces the risk of cerebral ischemia and is currently the only effective drug for the prevention of vasospasm in aSAH patients. DESIGN/METHODS: We retrospectively analyzed 109 patients with aSAH admitted to the Neurosciences Intensive Care Unit (NICU) at a tertiary care medical center between 2010 and 2013. Nimodipine-prescribing patterns, days of therapy completed, and adverse effects were tabulated. Patients not initiated on nimodipine and reasons for prematurely stopping therapy were noted. RESULTS: One hundred two (93%) patients with aSAH were started on oral nimodipine upon admission to the NICU. Early death (3%) and hypotension (1%) were reasons why patients were not started on nimodipine. Only 36 (33%) patients received nimodipine, 60 mg orally every 4 hours for 21 days. In 26 patients (39%), the dose of nimodipine was reduced because of excessive drops in blood pressure. Transient discontinuation occurred in 2 (2%) patients. Thirty one (47%) patients were discharged from the hospital before 21 days and nimodipine was not ordered to continue at home. CONCLUSION: We found that the majority of patients with aSAH in our practice did not complete 21 days of nimodipine. Hypotension was mostly responsible for dosing change or discontinuation.

Impact of Early Versus Late Intravenous Followed by Oral Nimodipine Treatment on the Occurrence of Delayed Cerebral Ischemia Among Patients With Aneurysm Subarachnoid Hemorrhage.

BACKGROUND: Guidelines for aneurysm subarachnoid hemorrhage (aSAH) management recommend treatment with nimodipine to all patients to reduce delayed cerebral ischemia (DCI) and poor clinical outcome. However, it did not give the most beneficial time to start therapy and route of administration. OBJECTIVES: To compare the DCI occurrence and clinical outcome among aSAH patients who received nimodipine treatment at different times. METHODS: A retrospective cohort study was conducted by collecting data from medical chart reviews between August 30, 2010, and October 31, 2015, at Prasart Neurological Institute, Thailand. Patients were classified into 2 groups by time to receive nimodipine: early group and late group (<96 and >96 hours, respectively). All patients received intravenous (IV) followed by oral nimodipine to complete treatment course. Clinical outcome was graded using the Glasgow Outcome Scale at 21 days. The factors related to DCI were analyzed using multivariate logistic regression. RESULTS: A total of 149 patients were recruited: early (n = 97) and late (n = 52). No difference in baseline characteristics between groups was observed. The occurrence of DCI was not statistically significantly different between groups (early group, 18.60%, vs late group, 20.80%; P = 0.74). The World Federation of Neurosurgical Societies IV to V was associated with DCI occurrence. The proportion of patients with good outcome, poor outcome, or death did not show any difference between groups. CONCLUSIONS AND RELEVANCE: Receiving IV nimodipine 3 to 7 days following oral therapy after bleeding can be the alternative regimen in patients who did not start nimodipine within 96 hours.

Side Effects of Long-Term Continuous Intra-arterial Nimodipine Infusion in Patients with Severe Refractory Cerebral Vasospasm after Subarachnoid Hemorrhage.

BACKGROUND: Long-term continuous intra-arterial nimodipine infusion (CIAN) is a rescue therapy option in cases of severe refractory cerebral vasospasm (CV) following acute non-traumatic subarachnoid hemorrhage (SAH). However, CIAN therapy can be associated with relevant side effects. Available studies focus on intracerebral complications, whereas extracerebral side effects are rarely examined. Aim of the present study was to generate descriptive data on the clinical course during CIAN therapy and expectable extracerebral side effects. METHODS: All patients treated with CIAN therapy for at least 5 days between May 2011 and December 2015 were included. We retrospectively extracted data from the patient data management system regarding the period between 2 days before the beginning and 5 days after the termination of CIAN therapy to analyze the course of ventilation parameters and pulmonary gas exchange, hemodynamic support, renal and liver function, integrity of the gastrointestinal tract, and the occurrence of infectious complications. In addition, we recorded the mean daily values of intracranial pressure (ICP) and intracerebral problems associated with CIAN therapy. RESULTS: Data from 28 patients meeting inclusion criteria were analyzed. The mean duration of long-term CIAN therapy was 10.5 ± 4.5 days. Seventeen patients (60.7%) reached a good outcome level (Glasgow Outcome Scale [GOS] 4-5) 6 months after SAH. An impairment of the pulmonary gas exchange occurred only at the very beginning of CIAN therapy. The required vasopressor support with norepinephrine was significantly higher on all days during and the first day after CIAN therapy compared to the situation before starting CIAN therapy. Two patients required short-time resuscitation due to cardiac arrest during CIAN therapy. Acute kidney injury was observed in four patients, and one of them required renal replacement therapy with sustained low-efficiency daily dialysis. During CIAN therapy, 23 patients (82.1%) needed the escalation of a previous antiinfective therapy or the onset of antibiotics which was in line with a significant increase of C-reactive protein and white blood cell count. Obstipation was observed in 22 patients (78.6%). Ten patients (35.7%) even showed insufficient defecation on at least seven consecutive days. Compared to the situation before, ICP was significantly higher during the whole period of CIAN therapy. CONCLUSIONS: Long-term CIAN therapy is associated with diverse side effects. The leading problems are an impairment of the hemodynamic situation and cardiac problems, an increase in infectious complications, a worsening of the motility of the gastrointestinal tract, and rising ICP values. Teams on neurointensive care units must be aware of these side effects to avoid that the beneficial effects of CIAN therapy on CV reported elsewhere are foiled by the problems this technique can be associated with.

Nimodipine Dose Reductions in the Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The incidence of cerebral infarction and poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH) is reduced by oral nimodipine but acute effects of the drug may include a significant decrease in mean arterial blood pressure (MAP). A dose reduction or discontinuation of the drug is recommended if recurrent MAP drops occur. The aim of our study was to evaluate the frequency and clinical significance of nimodipine dose modifications in patients suffering from aSAH. METHODS: 270 patients were included in our retrospective analysis of consecutively collected data of patients suffering from aSAH. The local treatment protocol was in accordance to national and international guidelines. Nimodipine was intended to be applied orally with a dosage of 60 mg every 4 h. RESULTS: Only 43.6 % of patients eligible for vasospasm prophylaxis with nimodipine received the full daily dose of 60 mg every 4 h. In 28.6 %, the dose had to be reduced by 50 % due to a significant reduction in blood pressure after administration and/or high dose of catecholamines. In 27.7 % of patients, oral administration of the drug was discontinued for the same reason. Dose reduction and discontinuation occurred with a significantly higher frequency in patients in poor clinical condition. Application of the full nimodipine dosage decreased the risk of unfavorable clinical outcome in multivariate analysis (OR 0.895, p = 0.029). CONCLUSIONS: Our results show that dose reduction or discontinuation of nimodipine due to changes in MAP occur frequently in clinical routine and may be associated with unfavorable clinical outcome.

Efficacy and safety assessment of acupuncture and nimodipine to treat mild cognitive impairment after cerebral infarction: a randomized controlled trial.

BACKGROUND: Cerebral infarction frequently leads to mild cognitive impairment (MCI). Prompt management of MCI can prevent vascular dementia and improve patient outcome. This single center randomized controlled trial aims to investigate the efficacy and safety of acupuncture and nimodipine to treat post-cerebral infarction MCI. METHODS: A total of 126 Chinese patients with post-cerebral infarction MCI recruited from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine between April 2013 and June 2014 were randomized at 1:1: 1 ratio into nimodipine alone (30 mg/time and 3 times daily), acupuncture alone (30 min/time, 6 times/week), and nimodipine + acupuncture groups. The treatments were 3 months. Cognitive function was evaluated using Montreal Cognitive Assessment (MoCA) scale at enrollment interview, at the end of 3-month therapy, and at the post-treatment 3-month follow-up. RESULTS: The per-protocol set included 39, 40, and 40 patients from nimodipine alone, acupuncture alone, and the combination group, respectively, was analyzed. Intra-group comparison revealed that MoCA score at the follow-up improved significantly by 15.8 ± 10.9, 20.9 ± 13.8 %, and 30.2 ± 19.7 % compared with the baseline MoCA for nimodipine alone, acupuncture alone, and the combination group, respectively. Inter-group comparison demonstrated that the combination therapy improved MoCA score (5.5 ± 2.2) at significantly higher extent than nimodipine alone (3.1 ± 1.8) and acupuncture alone (4.3 ± 2.3) at the follow-up (All P < 0.05), and significantly higher proportion of patients in acupuncture alone group (80 %) and the combination therapy group (90 %) than in nimodipine alone group (56.4 %) showed ≥12 % MoCA score improvement compared with the baseline MoCA (All P < 0.05). No adverse event was reported during the study. CONCLUSION: Acupuncture may be used as an additional therapy to conventional pharmacological treatment to further improve the clinical outcomes of patients with post-cerebral infarction MCI. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ , Unique Identifier: ChiCTR-IOR-15007366 ). The date of registration is November 4, 2015.

NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained-release microparticle formulation of nimodipine that has shown preclinical efficacy when administered intraventricularly or intracisternally to dogs with SAH, without evidence of toxicity at doses in the anticipated therapeutic range. Thus, we propose to administer EG-1962 to humans in order to assess safety and tolerability and determine a dose to investigate efficacy in subsequent clinical studies. METHODS: We describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of EG-1962 in patients with aSAH. The study will comprise two parts: a dose escalation period (Part 1) to determine the MTD of EG-1962 and a treatment period (Part 2) to assess the safety and tolerability of the selected dose of EG-1962. Patients with a ruptured saccular aneurysm treated by neurosurgical clipping or endovascular coiling will be considered for enrollment. Patients will be randomized to receive either EG-1962 (study drug: nimodipine microparticles) or oral nimodipine in the approved dose regimen (active control) within 60 h of aSAH. RESULTS: Primary objectives are to determine the MTD and the safety and tolerability of the selected dose of intraventricular EG-1962 as compared to enteral nimodipine. The secondary objective is to determine release and distribution by measuring plasma and CSF concentrations of nimodipine. Exploratory objectives are to determine the incidence of delayed cerebral infarction on computed tomography, clinical features of delayed cerebral ischemia, angiographic vasospasm, and incidence of rescue therapy and clinical outcome. Clinical outcome will be determined at 90 days after aSAH using the extended Glasgow outcome scale, modified Rankin scale, Montreal cognitive assessment, telephone interview of cognitive status, and Barthel index. CONCLUSION: Here, we describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the MTD and assess the safety and tolerability of EG-1962 in patients with aSAH.

Prospective investigation of nimodipine for acute vocal fold paralysis.

INTRODUCTION: Nimodipine has been shown to be beneficial for recovery from acute vocal fold paralysis (AVFP) in an animal model. METHODS: prospective, open-label trial of patients with AVFP was performed using nimodipine. Consecutive patients were evaluated and offered nimodipine therapy. RESULTS: Fifty-three patients were considered for treatment with nimodipine. Thirteen did not qualify for inclusion, 5 were lost to follow-up, and 7 had side effects requiring cessation of treatment. Thus 28 patients (30 paralyzed vocal folds) were analyzed. Eighteen of the paralyzed vocal folds experienced recovery of purposeful motion (60%). Historical controls and laryngeal electromyography meta-analysis suggest no more than a 20% recovery rate from AVFP. CONCLUSIONS: This open label study using nimodipine for treatment of AVFP demonstrates tripling of the recovery rate of vocal fold motion compared with historical controls. Further study in a randomized, controlled manner is warranted.

Nimodipine, a calcium channel blocker, delays the spontaneous LH surge in women with regular menstrual cycles: a prospective pilot study.

BACKGROUND: Currently GnRH analogue injections are used to prevent premature LH surges in women undergoing assisted reproductive technology. This was a pilot study to determine the safety and effectiveness of nimodipine, an oral calcium channel blocker, to delay the mid-cycle spontaneous LH surge in women with regular menstrual cycles. METHODS: Eight women with regular menstrual cycles self-monitored three consecutive cycles for the day of an LH surge by daily urine assay. The first and third cycles were observatory. In the second cycle, subjects took nimodipine 60 mg by mouth three times daily for four days, starting two days prior to the expected LH surge day based on cycle one. RESULTS: The LH surge day in cycle 2 (nimodipine) was significantly delayed in comparison to both observatory cycle 1 (15.5+/-3.4 vs 14.0+/-2.8 days; p=0.033) and cycle 3 (15.1+/-3.5 vs 13.1+/-2.4 days; p=0.044). There was no difference in the LH surge day between the two observatory cycles (13.4+/-2.4 vs 13.1+/-2.4 days; p=0.457). Three patients experienced a mild headache. CONCLUSIONS: There was a statistically significant delay in the spontaneous LH surge day in the treatment cycle in comparison to both observatory cycles. Nimopidine should be further investigated as an oral alternative to delay a spontaneous LH surge.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE).

BACKGROUND: Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia. METHODS/DESIGN: The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30-80 who have suffered an ischemic stroke (≤7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22%, at least 656 patients are required in this study to obtain statistical power of 90%. The first patient was recruited in November 2010. DISCUSSION: Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer's disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke.

Nimodipine down-regulates CGRP expression in the rat trigeminal nucleus caudalis.

L-type calcium channel blockers like verapamil are used in the prophylaxis of migraine. However, their effect on the expression of CGRP in the trigeminal nucleus caudalis (TNC) is unknown. It is important because an earlier study had shown that olcegepant, a CGRP receptor antagonist, acts at the level of the trigeminal spinal nucleus rather than the trigeminal ganglia. Nimodipine was used in the present study as it crosses the blood-brain barrier. The objective of the study was to determine the pattern of expression of calcitonin gene-related peptide (CGRP) in the TNC after administration of nimodipine and/or morphine. Wistar rats were injected with saline, morphine, nimodipine or morphine + nimodipine for 14 days. Subsequently, the lowest part of the medulla oblongata containing the spinal nucleus was removed and processed for immunohistochemical localization of CGRP. The density of expression was quantified using Image J software. The results were statistically analyzed. CGRP expression was noted over the superficial part of the TNC, which decreased significantly after nimodipine administration. Conversely, morphine produced an up-regulation. The expression was unchanged with reference to saline in the morphine + nimodipine treated group. Decreased expression of CGRP in the trigeminal nucleus caudalis after nimodipine is being reported for the first time. Also, whether CGRP expression can be used as a marker for predicting the therapeutic efficacy of an anti-migraine drug is currently being investigated.

Efficacy of Nimodipine Combined with Latanoprost in Treating Open-Angle Glaucoma and Its Influence on Ocular Hemodynamics and Visual Field Defects.

Background: Open-angle glaucoma is a common ophthalmic disease, which has a great impact on the vision of middle-aged and elderly people. Medication plays an important role in the treatment of glaucoma, so finding effective drug treatment is of great significance to improve the quality of life of glaucoma patients. Objective: To explore the curative effect of nimodipine combined with latanoprost in the treatment of open-angle glaucoma and its effect on ocular hemodynamics and visual field defects. Methods: This study retrospectively analyzed the clinical data of 87 patients with open-angle glaucoma who came to the Shanxi Province Fenyang Hospital and The First Affiliated Hospital of Shanxi Datong University for treatment from January 2019 to January 2021. According to different treatment plans, the patients were divided into two groups: an observation group (n = 46) treated with nimodipine combined with latanoprost, and a control group (n = 41) treated by latanoprost monotherapy. Treatment efficacy, hemodynamics, visual field defects, 24-hour peak intraocular pressure, binocular optic disc parameters, adverse reactions and quality of life were recorded and compared between two groups of patients. Results: The overall therapeutic effect of the observation group was significantly better than that in the control group. After treatment, ocular hemodynamics, visual field defects, 24-hour peak intraocular pressure, binocular optic disc parameters and life quality of both groups were obviously improved compared to those before treatment, with more significant improvements in the observation group. In addition, there was no significant difference in the incidence of adverse reactions between the two groups. Conclusion: Nimodipine combined with latanoprost eye drops is effective in the treatment of primary open-angle glaucoma, which could effectively improve the ocular hemodynamics and visual field defects of patients with fewer adverse reactions and higher safety. Therefore, it can be further promoted and used in clinical practice.

Efficacy and Safety of the Association of Nimodipine and Choline Alphoscerate in the Treatment of Cognitive Impairment in Patients with Cerebral Small Vessel Disease. The CONIVaD Trial.

BACKGROUND: No approved treatment is available for patients with vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD). OBJECTIVE: The CONIVaD (Choline Alphoscerate and Nimodipine in Vascular Dementia) study aimed to investigate the feasibility, efficacy, and safety of a combined treatment with choline alphoscerate and nimodipine in patients with SVD and mild-to-moderate cognitive impairment. METHODS: Within this pilot, single-center (university hospital), double-blinded, randomized clinical trial, patients were randomized to two arms: 1-year treatment with nimodipine 30 mg three times a day (TID) plus choline alphoscerate 600 mg twice a day (BID) (arm 1) or nimodipine 30 mg TID plus placebo BID (arm 2). Patients underwent an evaluation at baseline and after 12 months. Cognitive decline, defined as a ≥ 2-point loss on the Montreal Cognitive Assessment, was the primary endpoint. Functional, quality of life, other cognitive measures, and safety were secondary endpoints. Treatment adherence was measured by the count of medicine bottles returned by patients. RESULTS: Sixty-two patients were randomized (31 each arm). Fourteen patients (22%) dropped out for reasons including consent withdrawal (n = 9), adverse reactions (n = 4), and stroke (n = 1). Forty-eight patients (mean ± SD age 75.1 ± 6.8 years), well balanced between arms, completed the study. Regarding adherence, of the prescribed total drug dose, > 75% was taken by 96% of patients for choline alphoscerate, 87.5% for placebo, and 15% for nimodipine. No statistically significant differences were found between the treatment groups for the primary cognitive outcome, nor for the secondary outcomes. Eight patients had non-serious adverse reactions; five presented adverse events. CONCLUSION: Patients' adherence to treatment was low. With this limitation, the combined choline alphoscerate-nimodipine treatment showed no significant effect in our cohort of VCI patients with SVD. The safety profile was good overall. TRIAL REGISTRATION: Clinical Trial NCT03228498. Registered 25 July 2017.