Estimating radiation exposure of the brain of a physician with a protective flap in interventional radiology: A phantom study.

PURPOSE: The efficiency of protective equipment for the brain has not been verified at the left anterior oblique (LAO) position, which is commonly used in clinical procedures. The purpose of this study was to investigate radiation exposure of the brain in interventional radiology (IR) and the shielding ability of a new protective flap. METHODS: We made a flap that combined a protective cap with a left lateral face shield. The flap was made of tungsten-containing rubber (TCR). An anthropomorphic head phantom was placed at the physician's position, and air kerma rates (µGy/min and µGy/15s) were measured by electronic dosimeter at three locations: the surface of the left side of the head, and the left and right temporal lobes with the protective cap and the flap in fluoroscopy and cine modes. The X-ray tube was at the lower left side of the physician, and its angles were LAO60 and LAO60CAU40. The tube voltage (95-125 kV), tube current (4.7-732 mA), and air kerma rate (27.8-1078 mGy/min) were automatically adjusted by the X-ray system. We obtained the cap and the flap shielding efficiencies. RESULTS: In cine mode at LAO60CAU40, the shielding efficiencies on the surface of the left side of the head and left temporal lobe with the cap were 92.6% and 5.1%, respectively, and the corresponding shielding efficiencies with the flap were 92.5% and 86.1%, respectively. The flap can reduce radiation exposure of the brain more than the cap alone. CONCLUSIONS: At the left anterior oblique in interventional radiology, the flap can reduce exposure to the brain.

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26.

The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargoes into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low-affinity or monovalent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma. However, these studies have been performed with mouse-selective TfR antibodies that recognize different TfR epitopes and have varied binding characteristics. In this study, we evaluated serum pharmacokinetics and brain and CSF exposure of the rat TfR-binding antibody OX26 affinity variants, having KDs of 5 nM, 76 nM, 108 nM, and 174 nM, all binding the same epitope in bivalent format. Pharmacodynamic responses were tested in the Hargreaves chronic pain model after conjugation of OX26 affinity variants with the analgesic and antiepileptic peptide, galanin. OX26 variants with affinities of 76 nM and 108 nM showed enhanced brain and cerebrospinal fluid (CSF) exposure and higher potency in the Hargreaves model, compared to a 5 nM affinity variant; lowering affinity to 174 nM resulted in prolonged serum pharmacokinetics, but reduced brain and CSF exposure. The study demonstrates that binding affinity optimization of TfR-binding antibodies could improve their brain and CSF exposure even in the absence of monovalent TfR engagement.

Efficient brain uptake of piperine and its pharmacokinetics characterization after oral administration.

1. Piperine, the major biological active component in black pepper has been associated with miscellaneous pharmacological effects, especially on central nervous system. To correlate with its neurological activity, a comprehensive pharmacokinetic profile of piperine in brain, plasma and cerebrospinal fluid after oral administration in rats was investigated in this study. 2. It was noted that piperine could efficiently penetrate and homogeneously distribute into brain with similar pharmacokinetics profiles in each region. In addition, piperine concentrations in brain and plasma were found to be comparable with brain to plasma area under curve extrapolated to infinity (AUC0→∞) ratios of 0.95 and 1.10 for total concentration and unbound concentrations, respectively. Piperine also demonstrated high affinity toward brain tissue (98.4-98.5%) and plasma protein (96.2-97.8%) leading to a brain distribution volume of 36.32 ± 1.40 ml/g brain. Moreover, its efficient membrane permeability (P app values of 5.41 ± 0.40 × 10- 5 cm/s and 4.78 ± 0.16 × 10- 5 cm/s for basolateral to apical and apical to basolateral transport in Caco-2 monolayer model) and limited hepatic metabolism (Clint of 8.15 µl/min/mg) could also contribute to its quick and high extent brain exposure. 3. In summary, this study for the first time demonstrated high brain penetration potency of piperine could be resulted from its high brain tissue affinity and membrane permeability together with its limited liver metabolism.

Analysis of the influence of handset phone position on RF exposure of brain tissue.

Exposure to mobile phone radio frequency (RF) electromagnetic fields depends on many different parameters. For epidemiological studies investigating the risk of brain cancer linked to RF exposure from mobile phones, it is of great interest to characterize brain tissue exposure and to know which parameters this exposure is sensitive to. One such parameter is the position of the phone during communication. In this article, we analyze the influence of the phone position on the brain exposure by comparing the specific absorption rate (SAR) induced in the head by two different mobile phone models operating in Global System for Mobile Communications (GSM) frequency bands. To achieve this objective, 80 different phone positions were chosen using an experiment based on the Latin hypercube sampling (LHS) to select a representative set of positions. The averaged SAR over 10 g (SAR10 g) in the head, the averaged SAR over 1 g (SAR1 g ) in the brain, and the averaged SAR in different anatomical brain structures were estimated at 900 and 1800 MHz for the 80 positions. The results illustrate that SAR distributions inside the brain area are sensitive to the position of the mobile phone relative to the head. The results also show that for 5-10% of the studied positions the SAR10 g in the head and the SAR1 g in the brain can be 20% higher than the SAR estimated for the standard cheek position and that the Specific Anthropomorphic Mannequin (SAM) model is conservative for 95% of all the studied positions.

Considering developmental neurotoxicity in vitro data for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study.

Developmental neurotoxicity (DNT) is a potential hazard of chemicals. Recently, an in vitro testing battery (DNT IVB) was established to complement existing rodent in vivo approaches. Deltamethrin (DLT), a pyrethroid with a well-characterized neurotoxic mode of action, has been selected as a reference chemical to evaluate the performance of the DNT IVB. The present study provides context for evaluating the relevance of these DNT IVB results for the human health risk assessment of DLT by estimating potential human fetal brain concentrations after maternal exposure to DLT. We developed a physiologically based kinetic (PBK) model for rats which was then translated to humans considering realistic in vivo exposure conditions (acceptable daily intake [ADI] for DLT). To address existing uncertainties, we designed case studies considering the most relevant drivers of DLT uptake and distribution. Calculated human fetal brain concentrations were then compared with the lowest benchmark concentration achieved in the DNT IVB. The developed rat PBK model was validated on in vivo rat toxicokinetic data of DLT over a broad range of doses. The uncertainty based case study evaluation confirmed that repeated exposure to DLT at an ADI level would likely result in human fetal brain concentrations far below the in vitro benchmark. The presented results indicate that DLT concentrations in the human fetal brain are highly unlikely to reach concentrations associated with in vitro findings under realistic exposure conditions. Therefore, the new in vitro DNT results are considered to have no impact on the current risk assessment approach.

Non-brain-exposure Exoscopic and Endoscopic Volume Reduction Surgery for Benign Meningioma En Plaque in an Elderly Patient: A Case Report.

Meningioma en plaque (MEP) often needs invasive surgery to resect totally because of its widespread proliferation along the dura mater. We report a minimally invasive surgical technique for non-brain-exposure exoscopic and endoscopic volume reduction in an elderly patient with MEP. An 83-year-old woman presented with gait disturbance and cognitive dysfunction that had progressed over 6 months. Magnetic resonance imaging (MRI) revealed a large MEP on the right frontal lobe with peritumoral edema. On confirming the benign nature of the tumor (WHO grade 1) by biopsy, the main feeders and tumor were transarterially embolized. Volume reduction surgery was performed under the assistance of an exoscope and an endoscope while being careful not to expose and damage the cortex. Her symptoms completely resolved postoperatively. This surgical technique without exposing the brain may be a treatment choice for elderly patients with benign symptomatic convexity MEP.

Absorbed dose in the operator's brain in interventional radiology practices: evaluation through KAP value conversion factors.

In order to address the recent concerns over a possible increasing in brain tumour mortality among interventional radiologists and cardiologist, this work evaluated the exposure conditions of the operator's brain during interventional procedures using Monte Carlo simulations with anthropomorphic phantoms. The absorbed doses in several predefined segments of the operator's brain were estimated in a typical interventional radiology irradiation scenario. The doses were normalized to the KAP values simulated for ten X-ray beam qualities and four projections (PA, RAO 25°, LAO 25° and CRA 25°). For the interventional radiology scenario, because of the position of the operator, no difference was found in the exposure between the left and right regions of the brain for the first operator. However, for the second operator standing at a farer distance from the tube, the exposure of the left part of the brain is up to two times higher than that of the right part. The results are in agreement with dose measurements reported in the literature. The conversion factors, obtained as the absorbed dose per KAP, can be used to obtain a first estimate of the exposure of the brain of the operators during interventional procedures.

Synthesis and Characterization of Carbon-11 Labeled Iloperidone for Imaging of α1-Adrenoceptor in Brain.

α1-Adrenoceptor is implicated in numerous neuronal diseases. The development of new modulators targeting this receptor as well as the investigation of the role of α1-adrenoceptor in healthy and disease conditions, however, is hindered by the lack of specific positron emission tomography (PET) radiotracers. Iloperidone shows a high binding affinity to α1-adrenoceptor and moderate selectivity over other brain receptors. We report herein the synthesis and characterization of carbon-11 labeled iloperidone for imaging of α1-adrenoceptor in brain. The radiolabeling of [11C]iloperidone was carried out conveniently in one step by treating precursor with [11C]CH3I in DMF in the presence of K2CO3. Then, [11C]iloperidone was purified by semi-preparative HPLC, and characterized in C57BL/6 mice using PET/CT scanning. The desired product [11C]iloperidone was obtained in an average decay corrected radiochemical of 12% (n = 3) and over 99% radiochemical purity. The average molar radioactivity was 357 GBq/µmol with total synthetic time of 35-40 min. PET/CT scanning in C57BL/6 mice showed favorable pharmacokinetic properties and high brain exposure of [11C]iloperidone. Blocking experiments by pretreatment with the unlabeled iloperidone showed the significant blocking effects with about 25% reduction in brain uptake. These results suggested that [11C]iloperidone can serve as a lead compound for the further development of specific radiotracers for PET imaging of α1-adrenoceptor in brain clinically.

Comparable Intestinal and Hepatic First-Pass Effect of YL-IPA08 on the Bioavailability and Effective Brain Exposure, a Rapid Anti-PTSD and Anti-Depression Compound.

YL-IPA08, exerting rapid antidepressant-like and anxiolytic-like effects on behaviors by translocator protein (TSPO) mediation, is a novel compound that has been discovered and developed at our institute. Fit-for-purpose pharmacokinetic properties is urgently needed to be discovered as early as possible for a new compound. YL-IPA08 exhibited low bioavailability (∼6%) during the preliminary pharmacokinetics study in rats after oral administration. Our aim was to determine how metabolic disposition by microsomal P450 enzymes in liver and intestine limited YL-IPA08's bioavailability and further affected brain penetration to the target. Studies of in vitro metabolic stability and permeability combined with in vivo oral bioavailability, panel CYP inhibitor co-administration via different routes, and double cannulation rats were conducted to elucidate the intestinal and hepatic first-pass effect of YL-IPA08 on bioavailability. Unbound brain-to-plasma ratio (K p,uu ) in rats was determined at steady state. Results indicated that P450-mediated elimination appeared to be important for its extensive first-pass effect with comparative contribution of gut (35%) and liver (17%), and no significant species difference was observed. The unbound concentration of YL-IPA08 in rat brain (6.5 pg/ml) was estimated based on K p,uu (0.18) and was slightly higher than in vitro TSPO-binding activity (4.9 pg/ml). Based on the onset efficacy of YL-IPA08 toward TPSO in brain and K p,uu , therapeutic human plasma concentration was predicted to be ∼27.2 ng/ml would easily be reached even with unfavorable bioavailability.

Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer's disease.

Systemic organ dysfunction is one of the important issues for the patients with Alzheimer's disease (AD) and their caregivers. Recent evidences suggest that periodontitis is a possible risk factor for progression of AD and lipopolysaccharide derived from Porphyromonas gingivalis (Pg-LPS) which is a major periodontopathic bacteria induces cognitive impairment in mice. However, the precise relationships between the brain exposure of Pg-LPS and systemic organ dysfunction in AD patients are still undetermined. In this study, we investigated whether brain exposure of Pg-LPS induced systemic organ dysfunction in a model of AD mouse. We employed 6 (young) and 13 (middle-aged) months-old 5XFAD mice and 6 months-old littermate (LT) mice, and treated with intracerebroventricular (ICV) injection of 2 µg Pg-LPS or saline (vehicle). The animals were monitored cognitive functions (Y maze, nest building, and Morris water maze tests), motor functions (wire hang and rotarod tests), physical condition (symptom score), and blood pressure (BP). Twenty-eight days later, their organs were weighted and the organ damages were examined. Continuous ICV injection of 2 µg/day Pg-LPS increased ionized calcium binding adapter molecule-1 (Iba-1) and cluster of differentiation 3 (CD3) positive cells in periventricular area of 5XFAD mice without enhancement of cognitive impairment, amyloid ß protein deposition, expressions of phosphorylated nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2). In addition, the Pg-LPS lowered the latency of rotarod test in young 5XAD mice and also reduced symptom score and weight of gastrocnemius muscle in the middle-aged animals. Moreover, the Pg-LPS induced cardiac atrophy in both young and middle-aged 5XFAD mice, and increased Iba-1 positive cells in left ventricle of the young animals. On the other hand, single ICV injection of 2 µg Pg-LPS in 5XFAD and continuous injection of 2 µg/day Pg-LPS in LT mice did not show any positive findings. Our present results demonstrated that continuous brain exposure of Pg-LPS started sarcopenia and cardiac injury without enhancing cognitive impairment in AD model mice.

Pharmacokinetics and brain distribution of amitraz and its metabolites in rats.

Amitraz is an acaricide and insecticide widely used in agriculture and veterinary medicine. Although central nervous system (CNS) toxicity is one of major toxicities following oral ingestion of amitraz, the understanding of the cause of the toxicity is limited. This study evaluated the systemic and brain exposure of amitraz and its major metabolites, BTS27271, 2',4'-formoxylidide, and 2,4-dimethylaniline following administration of amitraz in male Sprague-Dawley rats. Significant metabolism of amitraz was observed following the intravenous and oral administration. Amitraz related metabolites were majority of the total exposure observed, especially following oral administration. BTS27271 had higher brain exposure than amitraz and its other metabolites, which was due to low plasma protein binding but high brain tissue binding of BTS27271. Since BTS27271 has similar or higher toxicity and α2-adrenoreceptor agonist potency than amitraz, its exposure in brain tissues may be the major cause of CNS toxicity of amitraz in animals and humans.

Matriderm for Management of Scalp Necrosis Following Surgical Treatment of Giant Parietal Encephalocele.

BACKGROUND: Management of encephaloceles is challenging when massive brain herniation is present. In such instances, an expansile cranioplasty may be attempted so as to preserve some herniated brain tissue. Complications such as wound dehiscence, cerebrospinal fluid leak, and scalp necrosis are postoperative concerns. The treatment of scalp necrosis with dural and brain exposure is certainly a challenge due to the complexity of flap techniques in such a young age. Herein we describe the use of a novel technique for the management of a scalp necrosis and dehiscence in an infant. CASE DESCRIPTION: A patient with a giant parietal encephalocele and massive brain herniation underwent an expansile cranioplasty. A large scalp necrosis ensued as a complication and later progressed to a suture dehiscence despite a new surgical intervention, with resultant brain exposure. A scalp reconstruction was subsequently performed using an artificial dermal substitute, laid directly onto the brain, followed by a split-thickness skin graft. We observed a rapid engraftment, without any further complications, with an acceptable cosmetic result in the long-term follow-up. CONCLUSION: A simple technique, such as the use of an artificial dermal matrix with simultaneous split-thickness skin graft, may be an effective treatment for the repair of scalp defects, even when coverage of exposed brain tissue is necessary, when no other techniques are found to be suitable.

A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

Mimicking brain tissue binding in an in vitro model of the blood-brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration.

Assessing the rate of drug delivery to the central nervous system (CNS) in vitro has been used for decades to predict whether CNS drug candidates are likely to attain their pharmacological targets, located within the brain parenchyma, at an effective dose. The predictive value of in vitro blood-brain barrier (BBB) models is therefore frequently assessed by comparing in vitro BBB permeability, usually quoted as the endothelial permeability coefficient (Pe) or apparent permeability (Papp), to their rate of BBB permeation measured in vivo, the latter being commonly assessed in rodents. In collaboration with AstraZeneca (DMPK department, Södertälje, Sweden), the in vitro BBB permeability (Papp and Pe) of 27 marketed CNS drugs has been determined using a bovine in vitro BBB model and compared to their in vivo permeability (Pvivo), obtained by rat in-situ brain perfusion. The latter was taken from published data from Summerfield et al. (2007). This comparison confirmed previous reports, showing a strong in vitro/in vivo correlation for hydrophilic compounds, characterized by low brain tissue binding and a weak correlation for lipophilic compounds, characterized by high brain tissue binding. This observation can be explained by the influence of brain tissue binding on the uptake of drugs into the CNS in vivo and the absence of possible brain tissue binding in vitro. The use of glial cells (GC) in the in vitro BBB model to mimic brain tissue binding and the introduction of a new calculation method for in vitro BBB permeability (Pvitro) resulted in a strong correlation between the in vitro and in vivo rate of BBB permeation for the whole set of compounds. These findings might facilitate further in vitro to in vivo extrapolation for CNS drug candidates.

Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties.

BACKGROUND AND PURPOSE: Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1-4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM-2571, were assessed in vivo. EXPERIMENTAL APPROACH: Pharmacological effects and pharmacokinetics of intraperitoneally administered DDPM-2571 were assessed in CD-1 mice. KEY RESULTS: DDPM-2571 was quickly distributed into the brain and was highly effective in the prevention of chemically-induced seizures (pentylenetetrazole and pilocarpine models) and 6-Hz convulsions. It demonstrated significant anxiolytic-like and antidepressant-like properties. DDPM-2571 had antinociceptive properties, both in the hot plate test and in the second phase of the formalin test. Within the dose range tested, it did not impair animals' motor skills, but it impaired cognition and potentiated scopolamine-induced cognitive deficits in the passive avoidance task. CONCLUSIONS AND IMPLICATIONS: Due to GAT1 inhibition, DDPM-2571 is effective in mouse models of chemically-induced seizures, anxiety, depression, acute and tonic pain. At biologically active doses, it does not impair animals' motor skills, but it might induce memory deficits. Taken together, DDPM-2571 can be regarded as a promising lead structure in the search for new centrally acting drugs and a potent pharmacological tool to study the biological role of GAT1.

Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure.

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.