Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage

2021 ◽  
Vol 134 (1) ◽  
pp. 95-101 ◽  
Author(s):  
R. Loch Macdonald ◽  
Daniel Hänggi ◽  
Poul Strange ◽  
Hans Jakob Steiger ◽  
J Mocco ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Sustained Release ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
External Ventricular Drain ◽  
Plasma Concentrations ◽  
Intraventricular Injection ◽  
World Federation ◽  
Maximum Plasma ◽  
Clinical Trial Registration ◽  
Sustained Release Formulation

OBJECTIVEThe objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).METHODSPatients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.RESULTSFifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.CONCLUSIONSPlasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

Abstract TP425: How do Different Outcome Measures Reflect Outcome After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Daniel Haenggi ◽  
Nima Etminan ◽  
Hans Jakob Steiger ◽  
R. Loch Macdonald ◽  
Stephan A Mayer ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Outcome Measures ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Phase 1 ◽  
External Ventricular Drain ◽  
Cognitive Status ◽  
World Federation ◽  
Cognitive Assessments ◽  
Dose Escalation Study ◽  
Sustained Release Formulation

Few treatments for aneurysmal subarachnoid hemorrhage (aSAH) have been effective in randomized clinical studies. One reason may be that the outcome measures used are not sensitive enough to detect efficacy of treatments in this disease. This hypothesis was examined by comparing 6 outcome measures for 72 patients with aSAH. Patients with aSAH who were World Federation of Neurological Surgeons grades 2 to 4 with an external ventricular drain inserted as part of standard of care were entered in a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose and safety and tolerability of a sustained release formulation of nimodipine (EG-1962, NEWTON study) in patients with aSAH. Clinical outcome was assessed at 90 days after aSAH using the extended Glasgow outcome scale (eGOS), modified Rankin scale (mRS), Montreal cognitive assessment (MoCA), telephone interview of cognitive status (TICS), NIHSS and Barthel index. The relationship between each outcome measure and the eGOS was plotted on arithmetic graphs (Figure). The eGOS and mRS gave very similar results. More detailed cognitive assessments (MoCA, TICS) were more exponential in shape with more variability. The NIHSS and Barthel had outcomes clustered towards the highest ends of the scales with distributions that did not discriminate as much as the eGOS or mRS. The MoCA and TICS gave similar results. It was concluded that the eGOS or mRS produce a similar and varying range of outcomes after aSAH, whereas cognitive assessments like the MoCA and TICS and scales designed for ischemic stroke like the NIHSS and BI are less discriminatory of outcomes after aSAH.

scholarly journals Neopterin plasma concentrations in patients with aneurysmal subarachnoid hemorrhage: correlation with infection and long-term outcome

2016 ◽  
Vol 124 (5) ◽  
pp. 1287-1299 ◽  
Author(s):  
Leire Azurmendi ◽  
Vincent Degos ◽  
Natalia Tiberti ◽  
Natacha Kapandji ◽  
Paola Sanchez-Peña ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Antibiotic Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
World Federation ◽  
Long Term Outcome ◽  
Poor Outcome ◽  
Positive Bacterial Culture

OBJECT Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high rates of mortality and morbidity. The main predictor for the poor outcome is the World Federation of Neurosurgical Societies (WFNS) scale. However, this scale does not take into account proinflammatory events, such as infection occurring after the aSAH, which could modify the long-term status of patients. The aim of this study was to evaluate neopterin as an inflammatory biomarker for outcome and infection prediction in aSAH patients. METHODS Plasma concentrations of neopterin were measured in 61 aSAH patients (22 male and 39 female; mean age [± SD] 52.8 ± 11.8 years) using a commercial ELISA kit. Samples were collected daily for 10 days. Outcome at 12 months was determined using the Glasgow Outcome Scale (GOS) and dichotomized as poor (GOS score 1, 2, or 3) or good (GOS score 4 or 5). Infection was determined by the presence of a positive bacterial culture. RESULTS Patients with poor outcome at 12 months had higher concentrations of neopterin than patients with good outcome. In the same way, patients who had an infection during the hospitalization had significantly higher concentrations of neopterin than patients without infection (p = 0.001). Moreover, neopterin concentrations were significantly (p < 0.008) elevated in infected patients 2 days before infection detection and antibiotic therapy. CONCLUSIONS Neopterin is an efficient outcome predictor after aSAH. Furthermore, it is able to differentiate between infected and uninfected patients as early as 2 days before clinical signs of infection, facilitating earlier antibiotic therapy and better management.

Variation of patient characteristics, management, and outcome with timing of surgery for aneurysmal subarachnoid hemorrhage

2011 ◽  
Vol 114 (4) ◽  
pp. 1045-1053 ◽  
Author(s):  
Kelly B. Mahaney ◽  
Michael M. Todd ◽  
James C. Torner
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Management Practices ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Timing Of Surgery ◽  
Early Surgery ◽  
Outcome Variable ◽  
Optimal Time ◽  
World Federation ◽  
Time Interval ◽  
Fisher Grade

ObjectThe past 30 years have seen a shift in the timing of surgery for aneurysmal subarachnoid hemorrhage (SAH). Earlier practices of delayed surgery that were intended to avoid less favorable surgical conditions have been replaced by a trend toward early surgery to minimize the risks associated with rebleeding and vasospasm. Yet, a consensus as to the optimal timing of surgery has not been reached. The authors hypothesized that earlier surgery, performed using contemporary neurosurgical and neuroanesthesia techniques, would be associated with better outcomes when using contemporary management practices, and sought to define the optimal time interval between SAH and surgery.MethodsData collected as part of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) were analyzed to investigate the relationship between timing of surgery and outcome at 3 months post-SAH. The IHAST enrolled 1001 patients in 30 neurosurgical centers between February 2000 and April 2003. All patients had a radiographically confirmed SAH, were World Federation of Neurosurgical Societies Grades I–III at the time of surgery, and underwent surgical clipping of the presumed culprit aneurysm within 14 days of the date of hemorrhage. Patients were seen at 90-day follow-up visits. The primary outcome variable was a Glasgow Outcome Scale score of 1 (good outcome). Intergroup differences in baseline, intraoperative, and postoperative variables were compared using the Fisher exact tests. Variables reported as means were compared with ANOVA. Multiple logistic regression was used for multivariate analysis, adjusting for covariates. A p value of less than 0.05 was considered to be significant.ResultsPatients who underwent surgery on Days 1 or 2 (early) or Days 7–14 (late) (Day 0 = date of SAH) fared better than patients who underwent surgery on Days 3–6 (intermediate). Specifically, the worst outcomes were observed in patients who underwent surgery on Days 3 and 4. Patients who had hydrocephalus or Fisher Grade 3 or 4 on admission head CT scans had better outcomes with early surgery than with intermediate or late surgery.ConclusionsEarly surgery, in good-grade patients within 48 hours of SAH, is associated with better outcomes than surgery performed in the 3- to 6-day posthemorrhage interval. Surgical treatment for aneurysmal SAH may be more hazardous during the 3- to 6-day interval, but this should be weighed against the risk of rebleeding.

scholarly journals Elevated Baseline C-Reactive Protein as a Predictor of Outcome After Aneurysmal Subarachnoid Hemorrhage

Neurosurgery ◽  
2015 ◽  
Vol 77 (5) ◽  
pp. 786-793 ◽  
Author(s):  
◽  
Carole L. Turner ◽  
Karol Budohoski ◽  
Christopher Smith ◽  
Peter J. Hutchinson ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
White Blood Cells ◽  
Cerebral Injury ◽  
World Federation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Poor Outcome ◽  
Fisher Grade ◽  
Good Grade

Abstract BACKGROUND: There remains a proportion of patients with unfavorable outcomes after aneurysmal subarachnoid hemorrhage, of particular relevance in those who present with a good clinical grade. A forewarning of those at risk provides an opportunity towards more intensive monitoring, investigation, and prophylactic treatment prior to the clinical manifestation of advancing cerebral injury. OBJECTIVE: To assess whether biochemical markers sampled in the first days after the initial hemorrhage can predict poor outcome. METHODS: All patients recruited to the multicenter Simvastatin in Aneurysmal Hemorrhage Trial (STASH) were included. Baseline biochemical profiles were taken between time of ictus and day 4 post ictus. The t-test compared outcomes, and a backwards stepwise binary logistic regression was used to determine the factors providing independent prediction of an unfavorable outcome. RESULTS: Baseline biochemical data were obtained in approximately 91% of cases from 803 patients. On admission, 73% of patients were good grade (World Federation of Neurological Surgeons grades 1 or 2); however, 84% had a Fisher grade 3 or 4 on computed tomographic scan. For patients presenting with good grade on admission, higher levels of C-reactive protein, glucose, and white blood cells and lower levels of hematocrit, albumin, and hemoglobin were associated with poor outcome at discharge. C-reactive protein was found to be an independent predictor of outcome for patients presenting in good grade. CONCLUSION: Early recording of C-reactive protein may prove useful in detecting those good grade patients who are at greater risk of clinical deterioration and poor outcome.

scholarly journals Pharmacokinetics of Sustained-release, Oral, and Subcutaneous Meloxicam over 72 Hours in Male Beagle Dogs

2020 ◽  
Vol 59 (6) ◽  
pp. 737-741
Author(s):  
Brian J Smith ◽  
Stephen M Kirschner ◽  
Lon V Kendall
Keyword(s):  
Sustained Release ◽  
Adult Male ◽  
Plasma Concentrations ◽  
Beagle Dogs ◽  
Release Formulation ◽  
Sustained Release Formulation ◽  
Subcutaneous Dose ◽  
Cynomolgus Macaques ◽  
Animal Handling ◽  
Time Point

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

scholarly journals Intrasylvian hematoma caused by ruptured middle cerebral artery aneurysms predicts recovery from poor-grade subarachnoid hemorrhage

2015 ◽  
Vol 123 (3) ◽  
pp. 686-692 ◽  
Author(s):  
Hitoshi Fukuda ◽  
Kosuke Hayashi ◽  
Takafumi Moriya ◽  
Satoru Nakashita ◽  
Benjamin W. Y. Lo ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Multivariable Analysis ◽  
World Federation ◽  
Poor Grade ◽  
Younger Age ◽  
Scale Scores ◽  
Cisternal Irrigation ◽  
Observational Cohort ◽  
Middle Cerebral Artery Aneurysms

OBJECT Intrasylvian hematoma (ISH) is a subtype of intracranial hematoma caused by aneurysmal rupture and often presents with a poor initial neurological grade; it is not well studied. The aim of this study was to elucidate outcomes of aneurysmal subarachnoid hemorrhage (SAH) with ISH. METHODS Data for 97 patients with poor-grade SAH (World Federation of Neurosurgical Societies Grade IV or V) were retrospectively analyzed from a single-center, prospective, observational cohort database. Ultra-early surgical clipping, removal of hematoma, external decompression for brain swelling, and prevention of vasospasm by cisternal irrigation with milrinone were combined as an aggressive treatment. Characteristics and clinical courses of SAH with ISH were identified. The authors also evaluated any correlations between poor admission-grade SAH and ISH with good functional outcome. RESULTS Patients with poor admission-grade SAH and with ISH were more likely to have initial cerebral edema (p < 0.001, Mann-Whitney U-test), which significantly resolved overtime (p < 0.001, Mann-Whitney U-test). These patients had a better chance of functional survival (modified Rankin Scale scores of 1–3; OR 5.75; 95% CI 1.36–24.3; p = 0.017) at 6 months after hospital discharge, after adjustment for potential confounders such as younger age and better initial neurological grade by multivariable analysis. CONCLUSIONS ISH predicted good functional recovery from poor-grade aneurysmal SAH.

scholarly journals Decompressive craniectomy in patients with cerebral infarction due to malignant vasospasm after aneurysmal subarachnoid hemorrhage

2012 ◽  
Vol 03 (03) ◽  
pp. 251-255 ◽  
Author(s):  
Saffet Tuzgen ◽  
Baris Kucukyuruk ◽  
Seckin Aydin ◽  
Fatma Ozlen ◽  
Osman Kizilkilic ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Infarction ◽  
Decompressive Craniectomy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Clinical Results ◽  
Cerebral Infarct ◽  
World Federation ◽  
Life Saving

ABSTRACT Aim: The authors present their experience and the clinical results in decompressive craniectomy (DC) in patients with vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Materials and Methods: Between 2002 and 2010, six patients underwent DC due to cerebral infarct and edema secondary to vasospasm after aneurysmal SAH. Four patients were male, and two were female. The age of patients ranged between 33 and 60 (mean: 47,6 ± 11,4). The follow up period ranged between 12 to 104 months (mean: 47,6 ± 36,6). The SAH grading according World Federation of Neurosurgeons (WFNS) score ranged between 3 to 5. Results: Last documented modified Rankin Score (mRS) ranged between 2 to 6. One patient died in the following year after decompression due to pneumonia and sepsis. Two patients had moderate disability (mRS of 4) and three patients continue their life with minimal deficit and no major dependency (mRS score 2 and 3). Conclusion: DC can be a life-saving procedure which provides a better outcome in patients with cerebral infarction secondary to vasospasm and SAH. However, the small number of the patients in this study is the main limitation of the accuracy of the results, and more studies with larger numbers are required to evaluate the efficiency of DC in this group of patients.

Sign in / Sign up

Export Citation Format

Share Document