Dataset Information

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

ABSTRACT: Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

SUBMITTER: Sadan O

PROVIDER: S-EPMC10614995 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Sadan Ofer O Jeong Yoo-Seong YS Cohen-Sadan Shany S Sathialingam Eashani E Buckley Erin M EM Kandiah Prem A PA Grossberg Jonathan A JA Asbury William W Jusko William J WJ Samuels Owen B OB

medRxiv : the preprint server for health sciences 20231018

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharma ...[more]

PMID: 37905152

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Project description:BackgroundProteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state.MethodsPatients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides.ResultsStatistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both α and β chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and -25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf.ConclusionsConsistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury.

Project description:BackgroundSpontaneous subarachnoid hemorrhage (SAH) often results in altered cerebrospinal fluid (CSF) flow and secondary hydrocephalus, yet the mechanisms behind these phenomena remain poorly understood. This study aimed to elucidate the impact of SAH on individual CSF flow patterns and their association with secondary hydrocephalus.MethodsIn patients who had experienced SAH, changes in CSF flow were assessed using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI) at the Sylvian aqueduct and cranio-cervical junction (CCJ). Within these regions of interest, volumetric CSF flow was determined for every pixel and net CSF flow volume and direction calculated. The presence of acute or chronic hydrocephalus was deemed from ventriculomegaly and need of CSF diversion. For comparison, we included healthy subjects and patients examined for different CSF diseases.ResultsTwenty-four SAH patients were enrolled, revealing a heterogeneous array of CSF flow alterations at the Sylvian aqueduct. The cardiac-cycle-linked CSF net flow in Sylvian aqueduct differed from the traditional figures of ventricular CSF production about 0.30-0.40 mL/min. In 15 out of 24 patients (62.5%), net CSF flow was retrograde from the fourth to the third and lateral ventricles, while it was upward at the cranio-cervical junction in 2 out of 2 patients (100%). The diverse CSF flow metrics did not distinguish between individuals with acute or chronic secondary hydrocephalus. In comparison, 4/4 healthy subjects showed antegrade net CSF flow in the Sylvian aqueduct and net upward CSF flow in CCJ. These net CSF flow measures also showed interindividual variability among other patients with CSF diseases.ConclusionsThere is considerable inter-individual variation in net CSF flow rates following SAH. Net CSF flow in the Sylvian aqueduct differs markedly from the traditional ventricular CSF production rates of 0.30-0.40 mL/min in SAH patients, but less so in healthy subjects. Furthermore, the cardiac-cycle-linked net CSF flow rates in Sylvian aqueduct and CCJ suggest an important role of extra-ventricular CSF production.

Project description:Biological aging may occur at different rates than chronological aging due to genetic, social, and environmental factors. DNA methylation (DNAm) age is thought to be a reliable measure of accelerated biological aging which has been linked to an array of poor health outcomes. Given the importance of chronological age in recovery following aneurysmal subarachnoid hemorrhage (aSAH), a type of stroke, DNAm age may also be an important biomarker of outcomes, further improving predictive models. Cerebrospinal fluid (CSF) is a unique tissue representing the local central nervous system environment post-aSAH. However, the validity of CSF DNAm age is unknown, and it is unclear which epigenetic clock is ideal to compute CSF DNAm age, particularly given changes in cell type heterogeneity (CTH) during the acute recovery period. Further, the stability of DNAm age post-aSAH, specifically, has not been examined and may improve our understanding of patient recovery post-aSAH. Therefore, the purpose of this study was to characterize CSF DNAm age over 14 days post-aSAH using four epigenetic clocks. Genome-wide DNAm data were available for two tissues: (1) CSF for N = 273 participants with serial sampling over 14 days post-aSAH (N = 850 samples) and (2) blood for a subset of n = 72 participants at one time point post-aSAH. DNAm age was calculated using the Horvath, Hannum, Levine, and "Improved Precision" (Zhang) epigenetic clocks. "Age acceleration" was computed as the residuals of DNAm age regressed on chronological age both with and without correcting for CTH. Using scatterplots, Pearson correlations, and group-based trajectory analysis, we examined the relationships between CSF DNAm age and chronological age, the concordance between DNAm ages calculated from CSF versus blood, and the stability (i.e., trajectories) of CSF DNAm age acceleration over time during recovery from aSAH. We observed moderate to strong correlations between CSF DNAm age and chronological age (R = 0.66 [Levine] to R = 0.97 [Zhang]), moderate to strong correlations between DNAm age in CSF versus blood (R = 0.69 [Levine] to R = 0.98 [Zhang]), and stable CSF age acceleration trajectories over 14 days post-aSAH in the Horvath and Zhang clocks (unadjusted for CTH), as well as the Hannum clock (adjusted for CTH). CSF DNAm age was generally stable post-aSAH. Although correlated, CSF DNAm age differs from blood DNAm age in the Horvath, Hannum, and Levine clocks, but not in the Zhang clock. Taken together, our results suggest that, of the clocks examined here, the Zhang clock is the most robust to CTH and is recommended for use in complex tissues such as CSF.

Dataset Information

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Publications

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

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