Dexanabinol (HU-211) in the treatment of severe closed head injury: A randomized, placebo-controlled, phase II clinical trial*

Knoller, Nachshon; Levi, Leon; Shoshan, Igal; Reichenthal, E; Razon, N.; Rappaport, Z. H.; Biegon, Anat

doi:10.1097/00003246-200203000-00009

Cited by 145 publications

(78 citation statements)

References 18 publications

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“…Dexanabinol, a synthetic cannabinoid with antioxidant, anti-inflammatory, and antiglutamatergic properties, has also undergone phase II testing in severe TBI patients. 115 Patients receiving this drug showed improvements in initial intracranial pressure, cerebral perfusion pressure, and systolic blood pressure, with a trend towards improved six-month outcome. These results have led to a phase III trial that is currently ongoing.…”

Section: Oxidative Damagementioning

confidence: 97%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

143

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Summary: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBIinflammation, oxidative injury, and iron-induced damage -and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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Section: Oxidative Damagementioning

confidence: 97%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

143

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“…66 -68 A phase II clinical study of 67 patients, 6-month post-injury follow-up, concluded that dexanabinol was safe and well tolerated in patients with severe TBI with significant control of ICP and cerebral perfusion pressure, and without lowering of SBP to less than 90 mmHg. 69 However, a phase III randomized placebo-controlled clinical study of dexanabinol in 861 TBI patients reported it to be safe but not efficacious. 10 Sex alters the incidence and recovery from TBI, with men experiencing more injury than women.…”

Section: Clinical Studiesmentioning

confidence: 99%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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Summary: Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.

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“…Treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without jeopardizing blood pressure. A trend toward faster and better neurologic outcome was also observed [244]. Further studies (phase III randomized, placebocontrolled clinical trial) showed that dexanabinol is safe, but not efficacious in treatment of TBI [245].…”

Section: Dexanabinolmentioning

confidence: 90%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Dexanabinol (HU-211) in the treatment of severe closed head injury: A randomized, placebo-controlled, phase II clinical trial*

Abstract: Dexanabinol was safe and well tolerated in severe head injury. The treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without jeopardizing blood pressure. A trend toward faster and better neurologic outcome was also observed.

Cited by 145 publications

References 18 publications

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Use of Magnesium in Traumatic Brain Injury

Ion Channels as Drug Targets in Central Nervous System Disorders

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