Trials In Traumatic Brain Injury Research Articles

Therapeutic Potential of Cannabinoids in CNS Disease

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.

Treatment of Closed-Head Injury

Dr. Matz has constructed a truly outstanding compilation of articles on the treatment of closed-head injury. From pre-hospital treatment to clinical trials for traumatic brain injury, all aspects of care are included in this issue. Finally, the future impact of research in this area is discussed. Dr. Matz and his contributors deserve the highest praise for creating a most impressive and informative issue of Seminars.

Dexanabinol: dexanabinone, HU 211, PA 50211, PRS 211007, sinnabidol.

Dexanabinol [HU 211, dexanabinone, sinnabidol, PA 50211, PRS 211007] is a synthetic, non-psychotropic tetrahydro-cannabinoid. Dexanabinol lacks cannabimimetic activity, and is a functional antagonist of the NMDA receptor with antioxidant and anti-tumour necrosis factor-alpha properties. Dexanabinol is in clinical trials for traumatic brain injury (head injuries), glaucoma and mild cognitive impairment, and is being investigated preclinically for its potential in the treatment of multiple sclerosis. Pharmos has a licensing agreement with the Hebrew University, Israel, and is seeking a partner for development and commercialisation of the dexanabinol family of compounds. The Financial Times (ft.com) reported in March 2001 that the market for brain trauma could be worth approximately 500 million US dollars, according to estimates by Pharmos. The company was said to have 26 million US dollars in capital at the time, most of which would be used taking dexanabinol through regulatory submission, according to the Financial Times.

Promising strategies to minimize secondary brain injury after head trauma.

To review novel therapeutic approaches in the treatment of severe traumatic brain injury. Eighty-three studies were reviewed specific to the treatment of traumatic brain injury, in either experimental models or in patients. Four therapeutic strategies appear to be the most promising approaches currently in clinical trials for severe traumatic brain injury: a) the novel pharmacologic agent dexanabinol; b) hypertonic saline; c) mild hypothermia; and d) decompressive craniectomy. Each of these therapies share the common feature of targeting multiple mechanisms, suggesting this may be an important factor to the development of a successful approach to severe traumatic brain injury.

Neuroprotection and traumatic brain injury: theoretical option or realistic proposition.

Preclinical studies have shown that treatment to limit secondary cell damage can significantly improve outcome after traumatic brain injury. In contrast, neuroprotection trials in human traumatic brain injury have failed to convincingly demonstrate therapeutic benefit. Recent literature has begun to address this discrepancy between preclinical and clinical trials. Perhaps the most important recent observations relate to the potential role of apoptosis in secondary brain injury. Because apoptosis peaks more than 24 h after injury, concepts about the therapeutic window for traumatic brain injury treatment have changed. Apoptosis and necrosis are in delicate balance and inhibition of one cell death pathway may enhance the other. This raises questions about the ultimate effectiveness of treatment strategies directed toward a single injury mechanism. In contrast to clinical head injury, which reflects a complex multi-factorial disorder, animal models are generally designed to address only a single injury component and are performed in genetically inbred animals of a single sex. Moreover, animal studies usually employ pretreatment or early posttreatment administration, examine moderate rather than severe injury, fail to examine brain drug levels or treatment optimization, and do not use an intent-to-treat methodology. Recognition of these methodological differences between animal and human studies has led to new trial design proposals. For clinical studies, there should be better stratification of patients, a focus on moderate injury and earlier treatment, and larger sample sizes. Animal experiments should better parallel clinical studies and address therapeutic window and treatment optimization. Recognition of multiple cell death pathways should lead to new treatment strategies--including both combination drug treatment and drugs that affect multiple components of the secondary injury cascade.

Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (competitive receptor antagonists, ion channel blockers, and glycine antagonists)--such as selfotel, aptiganel, eliprodil, licostinel and gavestinel--failed to show efficacy in clinical trials of stroke or traumatic brain injury. This failure has been attributed to the deficient properties of the molecules that entered human trials and to inappropriate design of clinical studies. In this article we hypothesise that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival. We propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival.

Outcome measures for clinical trials in neurotrauma

Under the auspices of the American Brain Injury Consortium and the Joint Section of Neurotrauma and Critical Care of the American Association of Neurological Surgeons, the authors have reviewed and formulated opinions based on the evidence on protocol design and the outcome measures used for clinical trials in patients with a severe or moderate traumatic brain injury (TBI). First, in view of the heterogeneity of the population under study, the authors suggest that block randomization and stratification should always be used in the design of neurotrauma trials. Second, although the Glasgow Outcome Scale (GOS) remains the most widely used and accepted instrument for TBI trials, the authors believe the eight-point expanded scale that has recently been designed will ultimately provide greater discrimination, and narrower categories and will ultimately prove superior for detecting more subtle changes in outcome. Furthermore, the authors recommend, in view of the profound cognitive impairment in survivors of TBI, that neuropsychological tests be explored further as an adjunct to the GOS. Future research should focus on the development of more sensitive and specific surrogate outcome measures such as magnetic resonance imaging, neurochemical, neuropsychological, and quality of life measures in order to detect a neuroprotective effect in patients with TBI.

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Dexanabinol (HU-211): A nonpsychotropic cannabinoid with neuroprotective properties

The synthetic cannabinoid (+)-(6aS,10aS)-11-hydroxy-Δ-8-tetrahydrocannabinol 1′,1′-dimethylheptyl (dexanabinol, HU-211) is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. HU-211 inhibits the synthesis of tumor necrosis factor alpha (TNFα) and possesses antioxidant properties. HU-211 blocked NMDA-induced 45Ca uptake by primary neuronal cultures of rat forebrain and protected the same neuronal cultures against NMDA and glutamate neurotoxicity. Moreover, HU-211 effectively scavenged peroxy radicals in vitro and protected cultured neurons from the toxic effects of reactive oxygen species (ROS). In addition, HU-211 markedly suppressed in vitro TNFα production and nitric oxide (NO) generation (by >90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to lipopolysaccharide (LPS). Since glutamate, ROS and TNFα are implicated in the pathophysiology of various acute conditions, the promising results showing neuroprotection by HU-211, acting via multiple mechanisms, led to a series of studies in which the drug was given to experimental animals. In the present review we discuss results from experiments describing the potential use of HU-211 as a neuroprotective agent in models of traumatic brain injury, stroke, optic nerve injury, pneumacocal meningitis, sepsis, and soman toxicity. In addition, HU-211 was introduced into clinical trials for traumatic brain injury and the successful results of two phases of clinical trials in head injured patients are also shown. Drug Dev. Res. 50:211–215, 2000. © 2000 Wiley-Liss, Inc.

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies.

Laboratory studies have identified numerous potential therapeutic interventions that might have clinical application for the treatment of human traumatic brain injury. Many of these therapies have progressed into human clinical trials in severe traumatic brain injury. Numerous trials have been completed, and many others have been prematurely terminated or are currently in various phases of testing. The results of the completed Phase III trials have been generally disappointing, compared with the expectations produced by the successes of these interventions in animal laboratory studies. In this review, we summarize the current status of human traumatic brain injury clinical trials, as well as the animal laboratory studies that led to some of these trials. We summarize criteria for conducting clinical trials in severe traumatic brain injury, with suggestions for future improvements. We also attempt to identify factors that might contribute to the discrepancies between animal and human trials, and we propose recommendations that could help investigators avoid certain pitfalls in future clinical trials in traumatic brain injury.

Head injuries in four British neurosurgical centres

An issue in the design of trials in traumatic brain injury is whether variation amongst centres in 'conventional' management could mask the impact of a powerful new pharmacological agent. We report the results of an observational study of 988 patients admitted to one of four British neurosurgical units between 1986 and 1988 within 3 days of a severe head injury. The centres fell into two pairs on the basis of the 'intensity' of management. In Edinburgh and Southampton, more frequent use of intracranial pressure monitoring, ventilation and osmotic diuretics was made than in Glasgow and Liverpool. The odds ratio for an independent outcome at 6 months in Edinburgh or Southampton, relative to Glasgow or Liverpool, controlling for case mix, was 1.43 (95% CI, 1.03-1.98, p=0.033). Thus, there is weak evidence of an association between the approach to management and clinical outcome at 6 months.

Clinical trials in traumatic brain injury. What can we learn from previous studies?

Many compounds have now been tested that were expected to ameliorate the secondary ischemic brain damage after severe head injury. Thus far, none of these have been clearly successful. This review is an attempt to identify factors that could be responsible for some of these failures. Recommendations are made that could help to avoid these pitfalls in the future. The usefulness and criteria for use of animal models for traumatic brain injury to depict human head injury are discussed. Clearly, it has now become widely accepted that mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, are preferable in this heterogeneous patient population. Other factors, such as the effect of brain penetration, safety and tolerability of the compound, and the interface between the pharmaceutical industry and academics are a major influence in the success of these trials. Furthermore, different ways of analyzing trials such as sequential analysis and newer, alternative end points should be considered. Pharmacological agents will never be the "magic bullet" for a process as heterogenous in pathophysiological mechanisms as traumatic brain injury. This does not imply that the role of neuroprotective compounds will not be important in the future. New approaches in developing, conducting and analyzing these expensive clinical trials must be devised in the future.

Clinical neuro-protection trials in severe traumatic brain injury: lessons from previous studies.

Major advances have been made in understanding the pathophysiological events after severe human traumatic brain injury, and consequently, many compounds have been tested in clinical trials. Thus far, no Phase III trials have been clearly successful, in human neurotrauma, although several Phase II studies have shown apparent benefit. This review is an attempt to identify factors that could be responsible for some of these failures. Recommendations are made that attempt to avoid these pitfalls in the future. Five criteria for future conduct of clinical trials are proposed. The usefulness of animal models for traumatic brain injury and their ability are discussed. Clearly, it is now becoming accepted that mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, may be preferable in this heterogeneous patient population. The degree of brain penetration, the safety and tolerability of the compound, and end points used for outcome assessment are major influences upon the success of these trials. New approaches in developing, conducting, and analyzing these clinical trials should be considered in the future, if the costly failures of the past are not to be repeated, with the advent of newer "neuroprotective agents" and techniques.

Workshop on animal models of traumatic brain injury.

Workshop on animal models of traumatic brain injury.

Outcome measures for clinical trials involving traumatically brain-injured patients: report of a conference.

A conference was held in Houston, Texas, on October 8-9, 1991, to develop recommendations for outcome measures for clinical trials in traumatic brain injury. Participants, all experts in this area, discussed and agreed on treatments for patients with severe brain injury (Glasgow Coma Score [GCS] < or = 8) and moderate brain injury (GCS, 9-12). A parallel trial design was recommended rather than a factorial, sequential, or crossover design. It was agreed that stratifying randomization based on motor score alone or on a combination of motor score and age would result in increased power. Acute stage measurements, such as cerebral blood flow, cerebrospinal fluid biochemistry, and evoked potentials, were recommended only when they satisfied a specific hypothesis. Functional outcome measures were recommended as the primary outcome measure for severe brain injury (GCS, 3-8). Either the Glasgow Outcome Scale or Disability Rating Scale, measured at 6 months after injury, were recommended as the primary outcome measure for severe brain injury (GCS, < or = 8). For patients with moderately severe brain injury (GCS, 9-12), the Disability Rating Scale at 3 months after injury was recommended as the primary outcome measure. The Neurobehavioral Rating Scale appears to be a satisfactory instrument for measuring behavioral changes. Specific neuropsychological measures were recommended as supplementary outcome measures for both severe and moderate brain injury, consistent with a 1.5-hour period available for testing.

Outcome Measures for Clinical Trials Involving Traumatically Brain-Injured Patients

A CONFERENCE WAS held in Houston, Texas, on October 8–9, 1991, to develop recommendations for outcome measures for clinical trials in traumatic brain injury. Participants, all experts in this area, discussed and agreed on treatments for patients with severe brain injury (Glasgow Coma Score [GCS] ≤8) and moderate brain injury (GCS, 9–12). A parallel trial design was recommended rather than a factorial, sequential, or crossover design. It was agreed that stratifying randomization based on motor score alone or on a combination of motor score and age would result in increased power. Acute stage measurements, such as cerebral blood flow, cerebrospinal fluid biochemistry, and evoked potentials, were recommended only when they satisfied a specific hypothesis. Functional outcome measures were recommended as the primary outcome measure for severe brain injury (GCS, 3–8). Either the Glasgow Outcome Scale or Disability Rating Scale, measured at 6 months after injury, were recommended as the primary outcome measure for severe brain injury (GCS, ≤8). For patients with moderately severe brain injury (GCS, 9–12), the Disability Rating Scale at 3 months after injury was recommended as the primary outcome measure. The Neurobehavioral Rating Scale appears to be a satisfactory instrument for measuring behavioral changes. Specific neuropsychological measures were recommended as supplementary outcome measures for both severe and moderate brain injury, consistent with a 1.5-hour period available for testing.