Short Therapeutic Time Window Research Articles

A Biomimetic Nanoparticle Exerting Protection against Acute Liver Failure by Suppressing CYP2E1 Activity and Scavenging Excessive ROS.

Acute liver failure (ALF) is a severe liver disease caused by many reasons. One of them is the overdosed acetaminophen (APAP), which is metabolized into N-acetyl-p-benzoquinone imine (NAPQI), an excessive toxic metabolite, by CYP2E1, resulting in excessive reactive oxygen species (ROS), exhausted glutathione (GSH), and thereafter hepatocyte necrosis. N-acetylcysteine is the Food and Drug Administration-approved drug for detoxification of APAP, but it has limited clinical application due to the short therapeutic time window and concentration-related adverse effects. In this study, a carrier-free and bilirubin dotted nanoparticle (B/BG@N) is developed, which is formed using bilirubin and 18β-Glycyrrhetinic acid, and bovine serum albumin (BSA) is then adsorbed to mimic the in vivo behavior of the conjugated bilirubin for hitchhiking. The results demonstrate that B/BG@N can effectively reduce the production of NAPQI as well asexhibit antioxidant effects against intracellular oxidative stress via regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signal axis and reducing the production of inflammatory factors. In vivo study shows that B/BG@N can effectively improve the clinical symptom of the mice model. This study suggests that B/BG@N own increases circulation half-life, improves accumulation in the liver, and dual detoxification, providing a promising strategy for clinical ALF treatment.

Nanotechnology in Stroke: New Trails with Smaller Scales.

Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for effective treatment. During acute phase, intravenous administration of recombinant tissue plasminogen activator (tPA), a thrombolytic agent, and endovascular thrombectomy (EVT), a mechanical intervention to retrieve clots, are the only FDA-approved treatments to re-establish cerebral blood flow. Due to a short therapeutic time window and high potential risk of cerebral hemorrhage, a limited number of acute stroke patients benefit from tPA treatment. EVT can be performed within an extended time window, but such intervention is performed only in patients with occlusion in a larger, anatomically more proximal vasculature and is carried out at specialty centers. Regardless of the method, in case of successful recanalization, ischemia-reperfusion injury represents an additional challenge. Further, tPA disrupts the blood-brain barrier integrity and is neurotoxic, aggravating reperfusion injury. Nanoparticle-based approaches have the potential to circumvent some of the above issues and develop a thrombolytic agent that can be administered safely beyond the time window for tPA treatment. Different attributes of nanoparticles are also being explored to develop a multifunctional thrombolytic agent that, in addition to a thrombolytic agent, can contain therapeutics such as an anti-inflammatory, antioxidant, neuro/vasoprotective, or imaging agent, i.e., a theragnostic agent. The focus of this review is to highlight these advances as they relate to cerebrovascular conditions to improve clinical outcomes in stroke patients.

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments—selected mainly among repurposing drugs—able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.

Extracellular Vesicle Application as a Novel Therapeutic Strategy for Ischemic Stroke.

Ischemic stroke (IS) accounts for most of the cases of stroke onset, and due to short therapeutic time window for thrombolysis and numerous limited treatment measures and contraindications, lots of patients cannot receive satisfying therapeutic effects resulting in high disability and mortality worldly. In recent years, extracellular vesicles (EVs), as nanosized membrane-structured vesicles secreted from almost all cells, especially from stem/progenitor cells, have been reported to exert significant beneficial effects on IS from multiple approaches and notably ameliorate neurological outcome. Moreover, based on nano-size and lipid bilayer structure, EVs can easily penetrate the blood-brain barrier and migrate into the brain. In this review, we mainly systematically summarize the therapeutic effects of EVs on IS and explore their potential applications. Simultaneously, we also discuss administration routines, dosages, experimental observation time, and some key issues of EV application during IS treatment. It contributes to a comprehensive understanding of the progress of EV treatment for IS and providing confident evidence for further EV clinical application widely.

Telemedicine in Stroke Clinic during the COVID Era and the Challenges in Patient Management: Review Article

The ongoing COVID-19 challenge has disrupted the social, economic and health care system around the globe. As a result of this pandemic, social distancing policies have been strictly implemented creating an immense stress on health care services. Telemedicine is an evolving and a time-saving, logical and effective means for emergency patient assessment. In far flung areas, where local consulting stroke specialist are not available, telemedicine can act as an alternative tool for provision of suitable stroke care within the short and safe therapeutic time window. Telemedicine has a precious role in emergency stroke consultation. Specialists have ability to swiftly evaluate and supervise management of stroke patients via telemedicine in coordination with the remote physicians at the distant health units.

Targeted Delivery of Erythropoietin Hybridized with Magnetic Nanocarriers for the Treatment of Central Nervous System Injury: A Literature Review.

Although the incidence of central nervous system injuries has continued to rise, no promising treatments have been elucidated. Erythropoietin plays an important role in neuroprotection and neuroregeneration as well as in erythropoiesis. Moreover, the current worldwide use of erythropoietin in the treatment of hematologic diseases allows for its ready application in patients with central nervous system injuries. However, erythropoietin has a very short therapeutic time window (within 6–8 hours) after injury, and it has both hematopoietic and nonhematopoietic receptors, which exhibit heterogenic and phylogenetic differences. These differences lead to limited amounts of erythropoietin binding to in situ erythropoietin receptors. The lack of high-quality evidence for clinical use and the promising results of in vitro/in vivo models necessitate fast targeted delivery agents such as nanocarriers. Among current nanocarriers, noncovalent polymer-entrapping or polymer-adsorbing erythropoietin obtained by nanospray drying may be the most promising. With the incorporation of magnetic nanocarriers into an erythropoietin polymer, spatiotemporal external magnetic navigation is another area of great interest for targeted delivery within the therapeutic time window. Intravenous administration is the most readily used route. Manufactured erythropoietin nanocarriers should be clearly characterized using bioengineering analyses of the in vivo size distribution and the quality of entrapment or adsorption. Further preclinical trials are required to increase the therapeutic bioavailability (in vivo biological identity alteration, passage through the lung capillaries or the blood brain barrier, and timely degradation followed by removal of the nanocarriers from the body) and decrease the adverse effects (hematological complications, neurotoxicity, and cytotoxicity), especially of the nanocarrier.

Platelet Membrane Biomimetic Magnetic Nanocarriers for Targeted Delivery and in Situ Generation of Nitric Oxide in Early Ischemic Stroke.

Early diagnosis and treatment of acute ischemic stroke poses a significant challenge due to its suddenness and short therapeutic time window. Human endogenous cells derived biomimetic drug carriers have provided new options for stroke theranostics since these cells have higher biosafety and targeting abilities than artificial carriers. Inspired by natural platelets (PLTs) and their role in targeting adhesion to the damaged blood vessel during thrombus formation, we fabricated a biomimetic nanocarrier comprising a PLT membrane envelope loaded with l-arginine and γ-Fe2O3 magnetic nanoparticles (PAMNs) for thrombus-targeted delivery of l-arginine and in situ generation of nitric oxide (NO). Results demonstrate that the engineered 200 nm PAMNs inherit the natural properties of the PLT membrane and achieve rapid targeting to ischemic stroke lesions under the guidance of an external magnetic field. Subsequent to the release of l-arginine at the thrombus site, endothelial cells produce NO, which promotes vasodilation to disrupt the local PLT aggregation. Rapid targeting of PAMNs to stroke lesions as well as in situ generation of NO prompts vasodilation, recovery of blood flow, and reperfusion of the stroke microvascular. Thus, these PLT membrane derived nanocarriers are diagnostically beneficial for localizing stroke lesions and a promising modality for executing therapies.

Nasal Delivery of Antioxidants by Cholesterol-incorporated Liposomes Extends the Neuroprotective Time Window in Cerebral Ischemia.

Antioxidants have the potential to prevent cerebral ischemia-reperfusion (IR)-associated secondary damage induced by reactive oxygen species (ROS); however, the short therapeutic time window of IR is a considerable obstacle. Nano-sized nasal delivery systems provide an effective means of delivering drugs through the BBB, but few such systems have been developed to extend the treatment time window in IR. In this work, a nanosized nasal delivery system for antioxidants was found to have the potential to extend the neuroprotective time window. The authors chose to use the antioxidant C-phycocyanin (C-Pc) to design a neuroprotective liposome with a long life, controllable release, and high neuronal uptake rate. Liposomes formulated with various cholesterol to phospholipid ratios were assessed thermodynamically, kinetically, and biologically. Thermodynamically stable, monodispersive, and release-controllable C-Pc liposomes were more effectively taken up by Neuro2a cells than free C-Pc and were biocompatible, maintaining the anti-oxidative properties of C-Pc. When optimal C-Pc liposomes were administered to middle cerebral artery occlusion (MCAO) rats 2 h after onset, infarct sizes were smaller and behavioral activities improved compared with the same metrics in free C-Pc-treated rats. Liposomal delivery still reduced infarct sizes and improved behavioral activity 6 h after onset, whereas free C-Pc did not.

Endovascular Therapy: A Standard Treatment?

MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, THERAPY, THRACE: we are inundated by positive trials. In this issue of the Journal of Stroke (JOS), two important review papers are published. Dr. Ding nicely summarizes these results,1 while Dr. Yan and his colleagues emphasize the advancement of devices as one of the main reasons for the successful trials.2 Their messages are clear; endovascular therapy is helpful for treating stroke patients as long as appropriate patients are selected and good devices are used by skillful interventionalists. These recent series of trials will change the landscape of the neurology world. Although countries such as Korea already have actively used endovascular therapy, the endovascular strategy will soon spread worldwide. It is expected that increasing numbers of young physicians will choose to become endovascular specialists, device companies will prosper, and endovascular societies will strengthen. Accordingly, there will be a rapid increase in the number of comprehensive stroke centers equipped with advanced imaging tools and endovascular specialists. Undoubtedly, these factors will benefit stroke patients. However, this also means that medical costs will increase dramatically. Since excellent stroke centers armed with modern imaging tools and experienced interventionalists are costly even in affluent countries, such costs are likely to unacceptable in less affluent countries. Regardless of economic conditions, the costs will skyrocket globally as populations worldwide continue to age rapidly. In reality, the cost incurred by treating and preventing cerebrovascular diseases is already a significant burden to us; therefore, we must continue investigating less costly strategies. Endovascular therapy developed as a result of the defects of intravenous (IV) tissue plasminogen activator (t-PA), which has limited efficacy in re-canalizing occluded large arteries, has a very short therapeutic time window (<4.5 hours), and is associated with hemorrhagic complications unless administered early enough. To resolve these problems, drugs have been developed that are potentially more effective and safe than IV t-PA. One candidate is desmoteplase, which unfortunately does not yet have proven benefit. Several drugs such as minocycline are now being examined to determine whether they can reduce bleeding complications when used with IV t-PA. These and other drugs under development may increase the efficacy and safety or prolong the therapeutic time window of IV thrombolysis. I suspect that they may ultimately replace endovascular therapy, a more costly and complicated way of treatment, in the future. Although I fully agree with Drs. Ding and Yan, and am one of the most excited neurologists by these positive trials, I also worry that official acceptance of endovascular therapy as a standard treatment might prevent the proper examination of simpler, less expensive and potentially more effective treatments. We all know that potentially efficacious thrombolytics could not be tested in the early stage of stroke simply because IV t-PA has been designated a standard treatment. I hope my concern is groundless, and wish that you read this issue of the JOS comfortably.

Multimodal Nanoprobes Evaluating Physiological Pore Size of Brain Vasculatures in Ischemic Stroke Models

Ischemic stroke accounts for 80% strokes and originates from a reduction of cerebral blood flow (CBF) after vascular occlusion. For treatment, the first action is to restore CBF by thrombolytic agent recombinant tissue-type plasminogen activator (rt-PA). Although rt-PA benefits clinical outcome, its application is limited by short therapeutic time window and risk of brain hemorrhage. Different to thrombolytic agents, neuroprotectants reduce neurological injuries by blocking ischemic cascade events such as excitotoxicity and oxidative stress. Nano-neuroprotectants demonstrate higher therapeutic effect than small molecular analogues due to their prolonged circulation lifetime and disrupted blood-brain barrier (BBB) in ischemic region. Even enhanced BBB permeability in ischemic territories is verified, the pore size of ischemic vasculatures determining how large and how efficient the therapeutics can pass is barely studied. In this work, nanoprobes (NPs) with different diameters are developed. In vivo multimodal imaging indicates that NP uptakes in ischemic region depended on their diameters and the pore size upper limit of ischemic vasculatures is determined as 10-11 nm. Additionally, penumbra defined as salvageable ischemic tissues performed a higher BBB permeability than infarct core. This work provides a guideline for developing nano-neuroprotectants by taking advantage of the locally enhanced BBB permeability in ischemic brain tissues.

Review of Stroke Thrombolytics

The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).

Microvascular protection is essential for successful neuroprotection in stroke

Currently, the best way of neuroprotection for acute ischemic stroke appears to be restoration of blood flow to the ischemic area by thrombolysis. Unfortunately, a short therapeutic time window as well as thrombolysis-induced bleeding and edema limit the use of recanalization therapies. Here, we review the evidence suggesting that ischemia/reperfusion-induced microvascular injury plays a critical role in determining tissue survival after recanalization in focal cerebral ischemia by disrupting the blood-brain barrier integrity and promoting microcirculatory clogging. Among many complex mechanisms of the ischemia-reperfusion injury, overproduction of oxygen and nitrogen radicals on the microvascular wall appears to significantly contribute to these pathological processes. These developments bring about the exciting possibility that effective suppression of oxidative/nitrative stress during pharmacological or interventional re-opening of the occluded artery may significantly improve the outcome of recanalization therapies in stroke patients by improving microcirculatory reflow as well as by preventing hemorrhagic conversion and vasogenic edema. They also point to the critical (but partly neglected) importance of the microcirculation in neuroprotection.

Protective Effect of Delayed Remote Limb Ischemic Postconditioning: Role of Mitochondrial KATP Channels in a Rat Model of Focal Cerebral Ischemic Reperfusion Injury

Delayed remote ischemic postconditioning (DRIPost) has been shown to protect the rat brain from ischemic injury. However, extremely short therapeutic time windows hinder its translational use and the mechanism of action remains elusive. Because opening of the mitochondria KATP channel is crucial for cell apoptosis, we hypothesized that the neuroprotective effect of DRIPost may be associated with KATP channels. In the present study, the neuroprotective effects of DRIPost were investigated using adult male Sprague-Dawley rats. Rats were exposed to 90 minutes of middle cerebral artery occlusion followed by 72 hours of reperfusion. Delayed remote ischemic postconditioning was performed with three cycles of bilateral femoral artery occlusion/reperfusion for 5 minutes at 3 or 6 hours after reperfusion. Neurologic deficit scores and infarct volumes were assessed, and cellular apoptosis was monitored by terminal deoxynucleotidyl transferase nick-end labeling. Our results showed that DRIPost applied at 6 hours after reperfusion exerted neuroprotective effects. The KATP opener, diazoxide, protected rat brains from ischemic injury, while the KATP blocker, 5-hydroxydecanote, reversed the neuroprotective effects of DRIPost. These findings indicate that DRIPost reduces focal cerebral ischemic injury and that the neuroprotective effects of DRIPost may be achieved through opening of KATP channels.

A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice

Tissue plasminogen activator (t-PA) has a short therapeutic time window for administration (3 h) and carries a risk of promoting intracerebral hemorrhage. The aim of the present study was to investigate a therapeutic time window and frequency of hemorrhagic region by treatment with Stachybotrys microspora triprenyl phenol-7 (SMTP-7). Thrombotic occlusion was induced by transfer of acetic acid-induced thrombus at the right common carotid artery into the brain of mice. Infarction area, neurological score, edema percentage, and regional cerebral blood flow (CBF) were determined as the index of the efficacy of SMTP-7. In order to evaluate the mechanism of SMTP-7, plasmin activities and the expressions of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 mRNA were examined. SMTP-7 (0.1, 1, 10 mg/kg) dose dependently reduced infarction area, neurological score, and edema percentage. Additionally, its therapeutic time window was longer than that of t-PA, a high-molecular-weight compound. In addition, little hemorrhagic region was induced by treatment with SMTP-7. SMTP-7 showed plasmin activity in vivo and caused a decreased CBF to recover. Furthermore, the expressions of inflammatory cytokine mRNA (IL-1β, TNF-α, IL-6) were increased by t-PA treatment 3 h after ischemia but were not induced by SMTP-7 treatment. These results indicate that SMTP-7 shows potential thrombolytic and anti-inflammatory effects as well as a wide therapeutic time window and little hemorrhagic region compared with that of t-PA. Therefore, this novel low-molecular-weight compound may represent a novel approach for the treatment of cerebral infarction.

Feasibility and safety of remote radiology interpretation with telephone consultation for acute stroke in Thailand

"Telestroke" is emerging as a potential timesaving, efficient means for evaluating patients experiencing acute ischemic stroke. It provides an opportunity for administration of thrombolytic drugs within the short therapeutic time window associated with AIS. We describe our experiences of the feasibility and safety of remote radiology interpretation with telephone consultation. Thammasat Stroke Center employs a computed tomography-digital imaging and communication in medicine (CT-DICOM) image transfer by PACS (SYNAPSE-Fujifilm), providing a real-time CT image transferred directly to the stroke consultants. The patient data are communicated by traditional telephone conversation. Here, we assessed patients who received intravenous rt-PA treatment for ASI between October 2007 and January 2009. A total of 458 patients with AIS and transient ischemic attack (TIA) were admitted to a stroke unit during the study period. One hundred patients received intravenous rt-PA (21%). Median NIHSS before thrombolysis was 15 (3-34). Mean door-to-needle time was 54 minutes (15-125). Mean onset-to-treatment time OTT was 160 minutes (60-270). There were 13 asymptomatic intracerebral hemorrhages and two (one fatal) symptomatic intracerebral hemorrhages. At 3 months, 42 patients had achieved excellent recovery (mRS, 0-1) and 14 had died. Administration of rt-PA for AIS with remote radiology interpretation with telephone consultation was feasible and safe, and the system was well received. Further studies are needed to determine the benefit of this method as compared to the conventional telephone consultation alone.

Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model

Effective prophylaxis for post-traumatic epilepsy currently does not exist, and clinical trials using anticonvulsant drugs have yielded no long-term antiepileptogenic effects. We report that a single, rapid post-traumatic application of the proconvulsant cannabinoid type-1 (CB1) receptor antagonist SR141716A (Rimonabant-Acomplia) abolishes the long-term increase in seizure susceptibility caused by head injury in rats. These results indicate that, paradoxically, a seizure-enhancing drug may disrupt the epileptogenic process if applied within a short therapeutic time window.

Delayed Postconditioning Protects against Focal Ischemic Brain Injury in Rats

BackgroundWe and others have reported that rapid ischemic postconditioning, interrupting early reperfusion after stroke, reduces infarction in rats. However, its extremely short therapeutic time windows, from a few seconds to minutes after reperfusion, may hinder its clinical translation. Thus, in this study we explored if delayed postconditioning, which is conducted a few hours after reperfusion, offers protection against stroke.Methods and ResultsFocal ischemia was generated by 30 min occlusion of bilateral common carotid artery (CCA) combined with permanent occlusion of middle cerebral artery (MCA); delayed postconditioning was performed by repetitive, brief occlusion and release of the bilateral CCAs, or of the ipsilateral CCA alone. As a result, delayed postconditioning performed at 3h and 6h after stroke robustly reduced infarct size, with the strongest protection achieved by delayed postconditioning with 6 cycles of 15 min occlusion/15 min release of the ipsilateral CCA executed from 6h. We found that this delayed postconditioning provided long-term protection for up to two months by reducing infarction and improving outcomes of the behavioral tests; it also attenuated reduction in 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-uptake therefore improving metabolism, and reduced edema and blood brain barrier leakage. Reperfusion in ischemic stroke patients is usually achieved by tissue plasminogen activator (tPA) application, however, t-PA's side effect may worsen ischemic injury. Thus, we tested whether delayed postconditioning counteracts the exacerbating effect of t-PA. The results showed that delayed postconditioning mitigated the worsening effect of t-PA on infarction.ConclusionDelayed postconditioning reduced ischemic injury after focal ischemia, which opens a new research avenue for stroke therapy and its underlying protective mechanisms.

Inflammation in Acute Ischemic Stroke and its Relevance to Stroke Critical Care

Thrombolysis heralded a new era of acute intervention for ischemic stroke, accompanied by an increasing need for comprehensive acute critical care support. There remains the prospect of novel cerebral protection strategies. Cerebral ischemia initiates a complex cascade of events at genomic, molecular, and cellular levels, and inflammation is important in this cascade, both in the CNS and in the periphery. Closely linked events are induction of a classic acute phase protein response, activation of the hypothalamic-pituitary-adrenal axis (HPAA) and sympathetic nervous system (SNS), and rise in body temperature, all of which appear to importantly influence the outcome. Thrombolysis aside, various therapeutic strategies have been trialed without success recently, primarily directed at influencing neuronal activity and survival directly. Inflammation itself offers an attractive target, mainly because of its potential to exacerbate the spread of damage to the ischemic penumbra. A promising novel therapeutic approach is the interleukin-1 receptor antagonist (IL-1ra), which limits the action of the cytokine IL-1, a pivotal mediator in the pathophysiology of acute neurodegeneration. Critical care has much to offer some patients after acute ischemic stroke, including the delivery of acute interventions, often with very short therapeutic time windows, physiological support, and the management of complications. We discuss inflammation and its mediators in acute ischemic stroke, the systemic stress, and acute phase protein responses to acute ischemic stroke, how inflammation is relevant in deteriorating ischemic stroke, the impact of physiological variables, and both current and emerging interventions for acute ischemic stroke.

'No Time to be Lost!' Ethical considerations on consent for inclusion in emergency pharmacological research in severe traumatic brain injury in the European Union.

Severe Traumatic Brain Injury (TBI) remains a major cause of death and disability afflicting mostly young adult males and elderly people, resulting in high economic costs to society. Therapeutic approaches focus on reducing the risk on secondary brain injury. Specific ethical issues pertaining in clinical testing of pharmacological neuroprotective agents in TBI include the emergency nature of the research, the incapacity of the patients to informed consent before inclusion, short therapeutic time windows, and a risk-benefit ratio based on concept that in relation to the severity of the trauma, significant adverse side effects may be acceptable for possible beneficial treatments. Randomized controlled phase III trials investigating the safety and efficacy of agents in TBI with promising benefit, conducted in acute emergency situations with short therapeutic time windows, should allow randomization under deferred consent or waiver of consent. Making progress in knowledge of treatment in acute neurological and other intensive care conditions is only possible if national regulations and legislations allow waiver of consent or deferred consent for clinical trials.

Therapeutic Time Window of Methylprednisolone in Acoustic Injury

This study aims to investigate the therapeutic time window of methylprednisolone in acoustic injury. Although glucocorticoids have been widely used in the treatment of acoustic injury, the therapeutic time window of glucocorticoids in acoustic injury has never been examined. Mice were exposed to 4-kHz pure tone of 128-dB sound pressure level for 4 hours. Auditory brainstem response was examined before, immediately after, and 2 weeks after acoustic overexposure. Methylprednisolone significantly improved the auditory brainstem response threshold shifts 2 weeks after acoustic overexposure when it was administered before or immediately after acoustic overexposure, but not when administered 3 hours after acoustic overexposure. The present findings suggest that methylprednisolone possesses protective effects against acoustic injury of the cochlea with a short therapeutic time window.