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Current Neuropharmacology 2020Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine... (Review)
Review
Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine's role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.
Topics: Brain Injuries; Brain Injuries, Traumatic; Brain Ischemia; Calcium Channel Blockers; Humans; Nimodipine; Stroke
PubMed: 31560289
DOI: 10.2174/1570159X17666190927113021 -
Neurologia (Barcelona, Spain) 2014To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment.
OBJECTIVE
To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment.
MATERIAL AND METHODS
A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed.
RESULTS
The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm.
CONCLUSIONS
SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes.
Topics: Brain Ischemia; Cerebral Angiography; Humans; Intracranial Aneurysm; Magnetic Resonance Imaging; Nimodipine; Practice Guidelines as Topic; Risk Factors; Spinal Puncture; Subarachnoid Hemorrhage; Tomography, X-Ray Computed
PubMed: 23044408
DOI: 10.1016/j.nrl.2012.07.009 -
The Cochrane Database of Systematic... Jan 2012Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life.
OBJECTIVES
To review randomized trials of steroids for human acute spinal cord injury.
SEARCH METHODS
We searched the Cochrane Injuries Group Specialised Register (searched 02 Aug 2011), The Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library), MEDLINE (Ovid) 1948 to July Week 3 2011, EMBASE (Ovid) 1974 to 2011 week 17, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011, ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011 and PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011) for records added to PubMed in the last 90 days). Files of the National Acute Spinal Cord Injury Study (NASCIS) were reviewed (NASCIS was founded in 1977 and has tracked trials in this area since that date). We also searched the reference lists of relevant studies and previously published reviews.
SELECTION CRITERIA
All randomized controlled trials of steroid treatment for acute spinal cord injury in any language.
DATA COLLECTION AND ANALYSIS
One review author extracted data from trial reports. Japanese and French studies were found through NASCIS and additional data (e.g. SDs) were obtained from the original study authors.
MAIN RESULTS
Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolne trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy.
AUTHORS' CONCLUSIONS
High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury.
Topics: Anti-Inflammatory Agents; Drug Administration Schedule; Glucocorticoids; Humans; Methylprednisolone; Neuroprotective Agents; Nimodipine; Randomized Controlled Trials as Topic; Spinal Cord Injuries
PubMed: 22258943
DOI: 10.1002/14651858.CD001046.pub2 -
International Wound Journal Aug 2016The potential of several drugs for full-thickness skin burns has been investigated, but the treatment of such burns remains a challenge in plastic surgery. The present...
The potential of several drugs for full-thickness skin burns has been investigated, but the treatment of such burns remains a challenge in plastic surgery. The present study was designed to determine the effect of systemic and topical administration of piracetam and nimodipine on full-thickness skin burn wound healing. A total of 36 New Zealand male rabbits were divided into six groups. Full-thickness skin burns were produced in all the groups, except the control group. Piracetam was administered systemically (piracetam-IV) and topically (piracetam-C) for 14 days, and nimodipine was administered systemically (nimodipine-IV) and topically (nimodipine-C) over the burn wounds for 14 days. The sham group underwent burn injury but was not administered any drug. After 21 days, gross examination and histopathological analysis were performed and the results were compared statistically. Nimodipine-C and nimodipine-IV had no effect on burn wound healing. However, both piracetam-IV and piracetam-C significantly enhanced the healing of the full-thickness skin burn wounds, although the latter was more effective, useful and practical in burn wound healing. The histopathological features of the wounds in the piracetam-C group were closer to those of the control group than those of the other groups. Piracetam-C rather than piracetam-IV may promote full-thickness burn wound healing in rabbits.
Topics: Animals; Burns; Male; Nimodipine; Piracetam; Rabbits; Skin; Wound Healing
PubMed: 26192365
DOI: 10.1111/iwj.12478 -
Annals of Neurology Jul 2020Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability....
OBJECTIVE
Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models.
METHODS
A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE.
RESULTS
We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion.
INTERPRETATION
Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.
Topics: Animals; Calcium Channel Blockers; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Magnetic Resonance Imaging; Male; Myelin Sheath; Nimodipine; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 32293054
DOI: 10.1002/ana.25749 -
RoFo : Fortschritte Auf Dem Gebiete Der... Jan 2018
Topics: Adult; Cerebral Angiography; Computed Tomography Angiography; Diagnosis, Differential; Headache Disorders, Primary; Humans; Magnetic Resonance Imaging; Male; Nimodipine; Subarachnoid Hemorrhage; Syndrome; Vasoconstriction; Vasospasm, Intracranial
PubMed: 28950385
DOI: 10.1055/s-0043-119891 -
Translational Stroke Research Oct 2022Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral...
Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44-61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83-91%) of their baseline diameter, which was significant (p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model.
Topics: Animals; Micelles; Nimodipine; Rats; Subarachnoid Hemorrhage; Ultrasonography; Vasodilator Agents; Vasospasm, Intracranial
PubMed: 34988870
DOI: 10.1007/s12975-021-00979-1 -
Drugs & Aging Jun 2021No approved treatment is available for patients with vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD). (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Aged; Aged, 80 and over; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Glycerylphosphorylcholine; Humans; Nimodipine; Quality of Life
PubMed: 33855653
DOI: 10.1007/s40266-021-00852-8 -
Scientific Reports May 2021Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key...
Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose-response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (E), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.
Topics: Animals; Calcium Channel Blockers; Dantrolene; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Humans; Male; Muscle Contraction; Muscle Relaxants, Central; Muscle, Smooth, Vascular; Nimodipine; Rats; Serotonin; Streptozocin; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 33972638
DOI: 10.1038/s41598-021-89338-6 -
Arquivos de Neuro-psiquiatria Jul 2022Subarachnoid hemorrhage (SAH) is an uncommon and serious subtype of stroke, which leads to the loss of the patient's ability to produce and live for many years. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Subarachnoid hemorrhage (SAH) is an uncommon and serious subtype of stroke, which leads to the loss of the patient's ability to produce and live for many years.
OBJECTIVE
To investigate the clinical effect of nimodipine in the treatment of SAH.
METHODS
Electronic databases including China National Knowledge Infrastructure (CNKI), VIP, SinoMed, China Master's Theses Full-text Database (CMFD), China Doctoral Dissertations Full-text Database (CDFD), Cochrane Library, PubMed and Embase were searched from 2010 and 2021. All randomized controlled trials evaluating the efficacy of nimodipine in the treatment of SAH were included in our meta-analysis. The patients were divided into control group and treatment group. Meta-analysis was performed with Stata16.0 software.
RESULTS
A total of 10 studies were included. Compared with the control group, the treatment group had higher effective rate (OR = 3.21, 95% CI: 2.25, 4.58; < 0.001), and lower incidence of adverse reactions (OR = 0.35, 95% CI: 0.19, 0.67; = 0.001). Before treatment, no significant differences were identified in middle cerebral artery blood flow velocity and Glasgow coma scale (GCS) score between the two groups. However, after treatment, the middle cerebral artery blood flow velocity (SMD = -1.36, 95% CI: -2.28, -0.49; = 0.002) and GCS score (SMD = 1.24, 95% CI: 0.58, 1.89; < 0.001) in the treatment group were significantly better than those in the control group.
CONCLUSIONS
Nimodipine is effective in the treatment of SAH, lowering incidence of adverse reactions and therefore improving the prognosis of patients.
Topics: Glasgow Coma Scale; Humans; Nimodipine; Stroke; Subarachnoid Hemorrhage; Treatment Outcome
PubMed: 36254437
DOI: 10.1055/s-0042-1755301