Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

A role for protein arginine methyltransferase 7 in repetitive and mild traumatic brain injury.

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

The Impact of Capping Creatinine Clearance on Achieving Therapeutic Vancomycin Concentrations in Neurocritically Ill Patients with Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is associated with secondary complications, including infection, and patients with TBI often exhibit augmented renal clearance (ARC). This phenomenon has been associated with subtherapeutic levels of renally cleared drugs such as vancomycin, which is dosed based on body weight and creatinine clearance (CrCl). Many clinicians, however, cap CrCl at 120 mL/min/1.73 m2 when calculating vancomycin dosing regimens. We hypothesize that capping patient CrCl, as opposed to utilizing the non-capped CrCl, when determining vancomycin dosing schemes results in subtherapeutic serum trough concentrations in patients with TBI. METHODS: This was a retrospective study of adult patients with TBI admitted between April 2014 and December 2015 who received vancomycin. Population-based pharmacokinetic (PK) parameters using non-capped calculated CrCl and capped CrCl were compared with patient-specific PK parameters based on serum trough concentrations. RESULTS: Thirty-two patients with TBI were included in the study. ARC was suspected in 24 (75%) patients due to a median estimated CrCl at serum trough concentration of 167.3 (127.7-197.7) mL/min. The mean dosing regimen was 17.1 (13.2-19.2) mg/kg every 8 (8-8) h. There was no difference between the median measured trough concentration and predicted value using non-capped CrCl [10.4 (7.1-15.0) vs. 11.5 (7.8-13.7) mcg/mL; p = 0.7986]. The median measured trough concentration was significantly lower than the predicted trough concentration when calculated based on capping the CrCl at 120 mL/min/1.73 m2 [16.3 (15.3-22.0) vs. 11.5 (7.8-13.7) mcg/mL; p < 0.0001]. CONCLUSIONS: Patients with traumatic brain injury appeared to exhibit augmented renal clearance, leading to subtherapeutic vancomycin serum trough concentrations when doses were calculated using the traditional method of capping creatinine clearance at 120 mL/min/1.73 m2. Instead, utilizing patients' non-capped creatinine clearance when determining a vancomycin dosing regimen is more accurate and provides a better estimation of vancomycin pharmacokinetics and could be applied to other renally excreted medications.

Neoplastic Cerebral Aneurysm From Metastatic Nonsmall Cell Lung Carcinoma: Case Report and Literature Review.

BACKGROUND AND IMPORTANCE: Intracranial cerebral aneurysms secondary to neoplastic etiology are a very rare occurrence. There have only been 5 published reports of intracranial cerebral aneurysms secondary to metastatic lung cancer. Four of those five previously published reports have been secondary to nonsmall cell lung carcinoma, and only 1 case caused subarachnoid hemorrhage. To our knowledge, this is the first report of a lung cancer-associated superior cerebellar artery aneurysm. CLINICAL PRESENTATION: A 41-yr old male presented with right-sided cerebellar hemorrhage. Cerebral angiogram was negative, but he was noted to have an underlying nonsmall cell carcinoma. His workup revealed a left upper lobe mass consistent with a diagnosis of metastatic lung carcinoma. A few weeks later, the patient represented with subarachnoid hemorrhage from a left superior cerebellar artery aneurysm that was new in comparison with a magnetic resonance angiography 19 d earlier. The aneurysm was remote to the surgical site, and the patient had a negative infectious workup, making an iatrogenic pseudoaneurysm or mycotic aneurysm unlikely. In the setting of metastatic cancer, a neoplastic cerebral aneurysm was the presumptive diagnosis. CONCLUSION: Intracranial neoplastic cerebral aneurysms are extremely rare entities, and a rare cause of subarachnoid hemorrhage. This diagnosis should be considered in patients who present with concurrent metastatic cancer and cerebral aneurysm or aneurysmal subarachnoid hemorrhage. Early initiation of chemotherapy may be beneficial in reducing the risk of tumor-particle embolization, but more research needs to be conducted to better understand this rare phenomenon.

G Protein-regulated inducer of neurite outgrowth (GRIN) modulates Sprouty protein repression of mitogen-activated protein kinase (MAPK) activation by growth factor stimulation.

Gα(o/i) interacts directly with GRIN (G protein-regulated inducer of neurite outgrowth). Using the yeast two-hybrid system, we identified Sprouty2 as an interacting partner of GRIN. Gα(o) and Sprouty2 bind to overlapping regions of GRIN, thus competing for GRIN binding. Imaging experiments demonstrated that Gα(o) expression promoted GRIN translocation to the plasma membrane, whereas Sprouty2 expression failed to do so. Given the role of Sprouty2 in the regulation of growth factor-mediated MAPK activation, we examined the contribution of the GRIN-Sprouty2 interaction to CB1 cannabinoid receptor regulation of FGF receptor signaling. In Neuro-2A cells, a system that expresses all of the components endogenously, modulation of GRIN levels led to regulation of MAPK activation. Overexpression of GRIN potentiated FGF activation of MAPK and decreased tyrosine phosphorylation of Sprouty2. Pretreatment with G(o/i)-coupled CB1 receptor agonist attenuated subsequent FGF activation of MAPK. Decreased expression of GRIN both diminished FGF activation of MAPK and blocked CB1R attenuation of MAPK activation. These observations indicate that Gα(o) interacts with GRIN and outcompetes GRIN from bound Sprouty. Free Sprouty then in turn inhibits growth factor signaling. Thus, here we present a novel mechanism of how G(o/i)-coupled receptors can inhibit growth factor signaling to MAPK.

Biomarkers and vasospasm after aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage from the rupture of a saccular aneurysm is a devastating neurological disease that has a high morbidity and mortality not only from the initial hemorrhage, but also from the delayed complications, such as cerebral vasospasm. Cerebral vasospasm can lead to delayed ischemic injury 1 to 2 weeks after the initial hemorrhage. Although the pathophysiology of vasospasm has been described for decades, the molecular basis remains poorly understood. With the many advances in the past decade in the development of sensitive molecular biological techniques, imaging, biochemical purification, and protein identification, new insights are beginning to reveal the etiology of vasospasm. These findings will not only help to identify markers of vasospasm and prognostic outcome, but will also yield potential therapeutic targets for the treatment of this disease. This review focuses on the methods available for the identification of biological markers of vasospasm and their limitations, the current understanding as to the utility and prognostic significance of identified biomarkers, the utility of these biomarkers in predicting vasospasm and outcome, and future directions of research in this field.

Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.

Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.

Adult neurogenesis as a potential therapy for neurodegenerative diseases.

Neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), are progressive neurological diseases that affect millions of people worldwide. Recent identification and advances in our understanding of multi-potent neural stem cells/progenitors in the mature CNS has raised the possibility that these discoveries can be translated into an effective therapy for degenerative neurological disease.