Talampanel For Treatment Patient After Traumatic Brain Injuries Biology Essay

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Traumatic brain injury (TBI) is one of the leading causes of death and permanent disability. According to Centers for Disease Control and Prevention approximately 1.4 million people sustain a traumatic brain injury each year in the United States.

The purpose of this study is to determine if Talampanel (an AMPA receptor blocker) the new antiepileptic and neuroprotective agent is effective in preventing acute seizures and improve neurological recovery.

We propose to perform II phase clinical trial to evaluate the safety and the effectiveness of Talampanel in patients after TBI. Patients with TBI will be randomly assigned to two groups. Group 1 standard care and Group 2 standard care and Talampanel 25mg for 12 weeks after injury. All subjects will be followed for one year. Serial EEGs and MRIs will be taken to evaluate brain function

2. Company description

Hijar-Max Pharmaceuticals is a privately held life science company located in St. Louis, Missouri. Our investors include pharmaceutical-focused venture capital investors, company founders and individuals.

The company is focused on the discovery and development of novel therapeutics for patients suffering from diseases associated with central nervous system (CNS).

The company is applying novel technologies that will generate first-in-class therapeutics, thereby changing the standard of care for patients suffering from epilepsy, traumatic brain injures (TBI) acute pain, and other disorders of the nervous system.

Hijar-Max Pharmaceuticals has been funded in 2005. Since this time the company has identified and patented multiple development candidates that have shown strong efficacy, safety and pharmacologic characteristics. In December 2009 our company filed Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for lead compound, NH555.

The company has also ongoing and planned clinical trials in CNS indications. Recently, Hijar-Max Pharmaceuticals has successfully finished a phase II clinical study investigating neuroprotective effect of N1226 compound in patients after ischemic stroke. Figure 1 presents detailed company`s pipeline.

The company is led by a strong management team with significant drug development experience and a strong track record of success within the field of central nervous system. In 2008 Hijar-Max Pharmaceuticals established collaboration with Washington University in St. Louis which is one of the leading medical research institutions in the United States. In addition, Hijar-Max has established collaborative relationships with pharmaceutical companies outside the U.S. In November 2008 Hijer- Max Pharmaceutical entered into a license agreement with Teva Pharmaceutical to develop and commercialize Talampanel for treatment patient after traumatic brain injury.

We believe that our partnerships will enhance the company's ability to develop and commercialize our product candidates.

Fig. 2 Hijar-Max Pharmaceuticals pipeline.

2. Agent and Study Plan

AMPA receptors are activated by glutamate that mediated fast excitatory neurotransmission in the central nervous system (CNS). Therefore, in normal synaptic functioning, activation of AMPA receptors is critical in many aspects of brain function. However, in pathophisiological conditions in which excess of glutamine is release over-activation of AMPA receptors leads into necrotic and apoptotic neuronal death. This process of neuronal death is called excitotoxicity and involved Ca2+ influx through AMPA receptors into the neuron (1). It has been suggested that excitotoxicity could be involved in the pathogenesis of several e neurodegenerative diseases, such as ischaemia-hypoxia, epilepsy, traumatic brain injury, Parkinson`s disease, ALS (Amyotrophic lateral sclerosis) and other motor neuron diseases, in which the activity of glutamatergic neurotransmission is elevated (2). Therefore, AMPA receptor antagonists have a potential therapeutic value in the treatment of chronic and acute neurodegenerative diseases. To date, several compounds inhibiting AMPA receptors have been developed and characterized (3). Four of those compounds are currently undergoing clinical trials for the treatment of central nervous system disorders (Table 1).

Hijer- Max, Pharmaceuticals is particularly interested in the use of AMPA receptor antagonists as neuroprotectiv agents to treat patients after traumatic brain injury (TBI). According to National Institute of Health, TBI is defined as a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain. In TBI primary insult results in immediate mechanical damage (primary injury). It has been shown that the level of glutamate markedly increase early after primary injury inducing neuronal Ca2+ entry through glutamate-regulated receptors. Those biochemical and physiological events ultimately lead to neuronal death and results in a secondary injury that evolves over a period of hours to days, even months, after the primary insult. Thus, blockade of receptors activated by glutamate such as AMPA receptors may protect patients after TBI against secondary brain damage and finally improve functional outcome of TBI patients.

We believe that Talampanel {(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3] benzodiazepine} (Fig.2) a noncompetitive antagonist of the AMPA receptors may be used as a neuroprotective agent to prevent secondary brain damage in patients after TBI (5). Talampanel is orally active and well tolerated by healthy human subjects (maximum tolerated dose was 100 mg). It has also good bloodbrain penetration (7). Currently, Talampanel is being examined in patients with amyotrophic lateral sclerosis, adults with partial seizures, and patients with recurrent glioma or advanced Parkinson’s disease (6).

Fig.2 Molecular structure of Talampanel (4)

Talampanel was effective in reduction of seizures in patients with refractory partial seizures (7). Furthermore, it has been shown that this drug protects primary rat hipocampal neurons against gluamate-mediated excitotoxicity (8). Neuroprotective effect of Talampanel has been also demonstrated in vivo using various animal models (9). It is important to note that, Belayev et al. reported that talampanel therapy significantly reduces brain damage in rat model of TBI. In addition, preclinical studies done by our company confirmed neuroprotective effect of talampanel in various animal models of TBI (manuscript in preparation).

Based on the scientific rationale and a positive preclincal study using animas model of TBI, we hipotetized that Talampanel can 1- reduce acute seizures and prevent the development of epilepsy following TBI and 2- improve patients neurological recovery. To test this idea Hijer- Max, Pharmaceuticals proposes to preform II phase clinical trial to determine if Talampanel is effective in preventing acute seizures and improve neurological recovery in patients after TBI.

Table 1. AMPA receptor antagonists examined for CNS diseases indication (6)

AMPA receptor


Clinical indication

Phase of clinical trail

LY 300164

Parkinson`s disease

Phase II


Parkinson`s disease

Amyotrophic Lateral Sclerosis (ALS)


Brain activity

Phase II

Phase II

Phase II

Phase II


Parkinson`s disease

Post Traumatic Stress Disorder (PTSD)

Alcohol and Comorbid Cocaine Dependence



Traumatic Brain Injury (TBI)

Bipolar Disorder

Tourette Syndrome

Phase II

Phase IV

Phase II

Phase IV

Phase IV

Phase II

Phase III

Phase III

ZK 200715

Visual system

Phase I

1. Frandsen A, Schousboe A. (2003) AMPA receptor-mediated neurotoxicity: role of Ca2+ and desensitization. Neurochem Res. Oct;28(10):1495-9.

2. Doble A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. Mar;81(3):163-221.

3. Gitto R, Barraca ML, De Luca L, Chimiri A. (2004) New trends in development of AMPA receptor antagonists. Expert. Opin. Ther. Patents. 14 (8): 1199-1213.

4. www.chemblink.com

5. Howes JF, Bell C. (2007) Talampane. Neurotherapeutics. Jan;4(1):126-9.

6. www.clinicaltrials.gov

7. Chappell et al (2002) A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology (58)1680-1682

8. Belayev L et al (2001) Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats. J Neurotrauma. (10):1031-8.

9. Denes L, Szil´agyi G, G´al A, Nagy Z. (2006) Talampanel a non-competitive AMPA-antagonist attenuates caspase-3dependent apoptosis in mouse brain after transient focal cerebral ischemia. Brain Research Bulletin (70) 260â€"262.