Article

Prophylactic Intravenous Nimodipine Treatment in Skull Base Surgery: Pharmacokinetic Aspects

University of Halle-Wittenberg, Department of Neurosurgery, Halle (Saale), Germany.
Journal of neurological surgery. Part A, Central European neurosurgery 01/2012; 73(3):153-9. DOI: 10.1055/s-0032-1313724
Source: PubMed

ABSTRACT Nimodipine is primarily used in subarachnoid hemorrhage (SAH). Clinical trials revealed also a beneficial effect of prophylactic nimodipine treatment on cranial nerve functions following vestibular schwannoma surgery.
The unknown pharmacokinetics of prophylactically administered nimodipine were investigated.
Samples were taken from 27 patients with skull base lesions. Prophylactic intravenous nimodipine infusion was started 5.8-25.8 h (mean 17.9 h) before surgery. Nimodipine concentrations were determined in serum (intra- and postoperatively), cerebrospinal fluid (CSF) (intraoperatively), and tissue samples.
Wide interindividual differences were observed. Mean concentrations for nimodipine were 46.9 ng/ml (SD: 6.4; min. 4.1 and max. 92.7 ng/ml) in intraoperative serum, 73.2 ng/ml (SD: 16.7; min. 6.6 and max. 253 ng/ml) in postoperative serum and 8.3 ng/ml (SD: 1.5; min. 1.0 und max. 29.7 ng/ml) in intraoperative CSF. The correlation between intra- and postoperative serum (p=0.004, r=0.560) and between intra-operative serum and CSF concentration (p=0.003, r=0.567) were statistically significant. Furthermore the correlation between intraoperative serum concentration and concentrations collected from vestibular nerves was high (r=0.711), but not statistically significant (p=0.178).
Interindividually, continously administered intravenous nimodipine produces considerably variable serum levels. Controls of nimodipine serum concentrations may be useful to optimize nimodipine medication in skull base surgery and in the management of SAH. The serum nimodipine level is a useful marker for CSF and intracranial nerve tissue concentrations of nimodipine.

Full-text

Available from: Christian Scheller, Jan 16, 2014
0 Followers
 · 
136 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: International Journal of Developmental Neuroscience j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j d e v n e u Nimodipine enhances neurite outgrowth in dopaminergic brain slice co-cultures a b s t r a c t Calcium ions (Ca 2+) play important roles in neuroplasticity and the regeneration of nerves. Intracellular Ca 2+ concentrations are regulated by Ca 2+ channels, among them L-type voltage-gated Ca 2+ channels, which are inhibited by dihydropyridines like nimodipine. The purpose of this study was to investigate the effect of nimodipine on neurite growth during development and regeneration. As an appropriate model to study neurite growth, we chose organotypic brain slice co-cultures of the mesocortical dopaminergic projection system, consisting of the ventral tegmental area/substantia nigra and the prefrontal cortex from neonatal rat brains. Quantification of the density of the newly built neurites in the border region (region between the two cultivated slices) of the co-cultures revealed a growth promoting effect of nimodipine at concentrations of 0.1 ␮M and 1 ␮M that was even more pronounced than the effect of the growth factor NGF. This beneficial effect was absent when 10 ␮M nimodipine were applied. Toxicological tests revealed that the application of nimodipine at this higher concentration slightly induced caspase 3 activation in the cortical part of the co-cultures, but did neither affect the amount of lactate dehydrogenase release or propidium iodide uptake nor the ratio of bax/bcl-2. Furthermore, the expression levels of different genes were quantified after nimodipine treatment. The expression of Ca 2+ binding proteins, immediate early genes, glial fibrillary acidic protein, and myelin components did not change significantly after treatment, indicating that the regulation of their expression is not primarily involved in the observed nimodipine mediated neurite growth. In summary, this study revealed for the first time a neurite growth promoting effect of nimodipine in the mesocortical dopaminergic projection system that is highly dependent on the applied concentrations.
    International Journal of Developmental Neuroscience 11/2014; 40(40):1-11. DOI:10.1016/j.ijdevneu.2014.10.005 · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery. The mechanism of the protective competence of nimodipine is unknown. Therefore, in this study, we established an in vitro model to examine the survival of Neuro2a cells after different stress stimuli occurring during surgery with or without nimodipine. Nimodipine significantly decreased ethanol-induced cell death of cells up to approximately 9% in all tested concentrations. Heat-induced cell death was diminished by approximately 2.5% by nimodipine. Cell death induced by mechanical treatment was reduced up to 15% by nimodipine. Our findings indicate that nimodipine rescues Neuro2a cells faintly, but significantly, from ethanol-, heat- and mechanically-induced cell death to different extents in a dosage-dependent manner. This model seems suitable for further investigation of the molecular mechanisms involved in the neuroprotective signal pathways influenced by nimodipine.
    International Journal of Molecular Sciences 10/2014; 15(10-10):18453-18465. DOI:10.3390/ijms151018453 · 2.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and Study Aims/Object Oral nimodipine improves neurologic outcome after aneurysmal subarachnoid hemorrhage. In addition, the neuroprotective efficacy of nimodipine has been revealed following skull base, laryngeal, and maxillofacial surgery. Pharmacokinetic investigations showed nimodipine to reach higher serum levels following parenteral versus enteral administration. Furthermore, a correlation between nimodipine levels in serum, cerebrospinal fluid, and nerve tissue could be quantified. These observations raise the question whether the proven neuroprotective effect of nimodipine is related to its serum level. Patients/ Material and Methods A consecutive series of 37 patients with vestibular schwannoma treated with nimodipine from the day before surgery until the seventh postoperative day was analyzed retrospectively. Both groups received standard dosages for enteral (n = 17) and parenteral (n = 20) nimodipine medication. Nimodipine levels were measured in pre- and postoperative serum and cerebrospinal fluid samples. Cochlear and facial nerve functions were documented before surgery, in the early postoperative course, and 1 year after surgery. Results Facial nerve outcome was significantly better in the group with parenteral nimodipine medication (p = 0.038). Logistical regression analysis revealed a seven times smaller risk for a deterioration of facial nerve function in the group with parenteral treatment. There was no difference in hearing preservation between both groups despite tumor size tending to be larger in the parenteral group. Intraoperative (p = 0.004), postoperative (p = 0.001), and serum and cerebrospinal fluid (p = 0.024) nimodipine levels were significantly higher following parenteral administration as compared with enteral administration. Both groups were comparable regarding tumor size and extent of resection.
    10/2013; 75(4). DOI:10.1055/s-0033-1355164