Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain.

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.

Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging.

BACKGROUND: The cytokines interleukin-1 and tumor necrosis factor (TNF), and the cytokine blocker interleukin-1 receptor antagonist, all have been demonstrated to enter the cerebrospinal fluid (CSF) following peripheral administration. Recent reports of rapid clinical improvement in patients with Alzheimer's disease and related forms of dementia following perispinal administration of etanercept, a TNF antagonist, suggest that etanercept also has the ability to reach the brain CSF. To investigate, etanercept was labeled with a positron emitter to enable visualization of its intracranial distribution following peripheral administration by PET in an animal model. FINDINGS: Radiolabeling of etanercept with the PET emitter 64Cu was performed by DOTA (1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid) conjugation of etanercept, followed by column purification and 64Cu labeling. MicroPET imaging revealed accumulation of 64Cu-DOTA-etanercept within the lateral and third cerebral ventricles within minutes of peripheral perispinal administration in a normal rat anesthesized with isoflurane anesthesia, with concentration within the choroid plexus and into the CSF. CONCLUSION: Synthesis of 64Cu-DOTA-etanercept enabled visualization of its intracranial distribution by microPET imaging. MicroPET imaging documented rapid accumulation of 64Cu-DOTA-etanercept within the choroid plexus and the cerebrospinal fluid within the cerebral ventricles of a living rat after peripheral administration. Further study of the effects of etanercept and TNF at the level of the choroid plexus may yield valuable insights into the pathogenesis of Alzheimer's disease.

The value of drug repositioning in the current pharmaceutical market.

Drug repositioning is the process of developing new indications for existing drugs or biologics. Increasing interest in drug repositioning has occurred due to sustained high failure rates and costs involved in attempts to bring new drugs to market. It has been estimated that it may cost more than USD 800 million to develop a new drug de novo. In addition, due to regulatory requirements regarding safety, efficacy and quality, the time required to develop a new drug de novo has been estimated to be 10 to 17 years. De novo drug discovery has failed to efficiently supply pharmaceutical company pipelines. A rational approach to drug repositioning may include a cross-disciplinary focus on the elucidation of the mechanisms of disease, allowing matching of disease pathways with appropriately targeted therapeutic agents. Repurposed drugs or biologics have the advantage of decreased development costs and decreased time to launch due to previously collected pharmacokinetic, toxicology and safety data. For these reasons, repurposing should be a primary strategy in drug discovery for every broadly focused, research-based pharmaceutical company.

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease.

BACKGROUND: Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease. METHODS: This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25-50 mg, weekly by perispinal administration for six months. Two additional case studies are presented. RESULTS: Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented. CONCLUSION: In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.

Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.

Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention.

Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults.

BACKGROUND: Etanercept, a recombinant biologic anti-tumor necrosis factor (TNF)-alpha therapeutic, is approved for the treatment of certain autoimmune arthritides by subcutaneous (SC) injection. TNF-alpha has been suggested to play a central role in neuropathic pain and neuronal damage associated with intervertebral disc herniation. Directed local administration of etanercept, in anatomic proximity to the site of disc and neuronal abnormality, may result in an enhanced therapeutic response. OBJECTIVE: This study reviews findings from 2 patients with chronic, severe, discogenic cervical pain who were treated with a targeted cervical injection of etanercept with the objective of obtaining relief from their treatment-resistant pain. METHODS: In this uncontrolled, open-label study, the case histories of 2 patients (1 woman and 1 man) presenting with a history of chronic neck pain refractory to various treatments are reviewed. Both patients were treated with etanercept 25 mg by SC injection to the cervical region (case 1) or the posterior neck overlying the spine (case 2). RESULTS: Both patients experienced almost complete pain relief as assessed subjectively. In case 1, the Oswestry score decreased from 58 before treatment to 6 one day following treatment. In addition, 1 day after treatment the patient reported a subjective assessment of 98% pain improvement, 100% sensory improvement, and 100% weakness improvement. She has remained asymptomatic for >1 year. In case 2, the Oswestry score decreased from 44 before treatment to 4 two months after treatment. The patient reported 100% pain relief and 90% sensory improvement 1 day after treatment. At 8-month follow-up, pain improvement continued to be 100% and sensory improvements was 75%. CONCLUSIONS: Etanercept, delivered by targeted SC injection, may be of benefit for selected patients with resistant pain associated with cervical disc disease. Further study of this new treatment modality is warranted.

Perispinal TNF-alpha inhibition for discogenic pain.

OBJECTIVE: To examine the potential of etanercept, a biological inhibitor of tumour necrosis factor-alpha (TNF), delivered by perispinal administration, for the treatment of pain associated with intervertebral disc disease. METHODS: Charts from 20 selected patients treated at our private clinic by perispinal delivery of etanercept 25 mg for severe, chronic, treatment-resistant discogenic pain were reviewed. Therapeutic benefit was assessed clinically and was documented by changes in a validated pain instrument, the Oswestry Disability Index. The patients were treated off-label with etanercept as part of our usual practice of medicine. Five detailed case reports are presented, including three additional patients. RESULTS: Rapid, substantial and sustained clinical pain reduction was documented in this selected group of patients. The cohort of 20 patients had a mean age of 56.5 and mean duration of pain of 116 months. Nine of the patients had undergone previous spinal surgery; 17 had received an epidural steroid injection or injections (mean 3.2). This group of patients received a mean of 1.8 doses (range 1-5, median 1.0) of etanercept during the observation period. The mean length of follow-up was 230 days. Clinical improvement was confirmed by a decrease in the calculated Oswestry Disability Index from a mean of 54.85 +/- 12.5 at baseline, improving to 17.2 +/- 15.3 (p <0.003) at 24 days and ending at 9.8 +/- 13 (p <0.003) at 230 days. CONCLUSIONS: TNF inhibition by etanercept delivered by perispinal administration may offer clinical benefit for patients with chronic, treatment-resistant discogenic pain. Further study of this new treatment modality is warranted.