Arguments to develop TRPV1 antagonist in neuropathic pain. Lessons for drug development

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Jan M Keppel Hesselink
Keyword(s):  
Neuropathic Pain ◽  
Drug Development ◽  
Trpv1 Antagonist

scholarly journals LASSBio-1135: A Dual TRPV1 Antagonist and Anti-TNF-Alpha Compound Orally Effective in Models of Inflammatory and Neuropathic Pain

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e99510 ◽  
Author(s):  
Cleverton K. F. Lima ◽  
Rafael M. Silva ◽  
Renata B. Lacerda ◽  
Bruna L. R. Santos ◽  
Rafaela V. Silva ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tnf Alpha ◽  
Trpv1 Antagonist

scholarly journals Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging

2016 ◽  
Vol 124 (1) ◽  
pp. 159-168 ◽  
Author(s):  
Vishvarani Wanigasekera ◽  
Melvin Mezue ◽  
Jesper Andersson ◽  
Yazhuo Kong ◽  
Irene Tracey
Keyword(s):  
Neuropathic Pain ◽  
Functional Connectivity ◽  
Drug Development ◽  
Somatosensory Cortex ◽  
Outcome Measures ◽  
Neural Activity ◽  
Resting State ◽  
Central Sensitization ◽  
Resting State Functional Connectivity ◽  
Secondary Somatosensory Cortex

Abstract Background Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. Methods The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Results Only gabapentin suppressed the secondary mechanical hyperalgesia–evoked neural response in a region of the brainstem’s descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Conclusions Functional imaging with central sensitization can be used as a sensitive mechanism–based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.

scholarly journals Lyophilization Serves as an Effective Strategy for Drug Development of the α9α10 Nicotinic Acetylcholine Receptor Antagonist α-Conotoxin GeXIVA[1,2]

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 121
Author(s):  
Zhiguo Li ◽  
Xiaolu Han ◽  
Xiaoxuan Hong ◽  
Xianfu Li ◽  
Jing Gao ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Drug Development ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Analgesic Effect ◽  
Tail Flick ◽  
Clinical Use ◽  
Effective Strategy ◽  
Scanning Calorimetry ◽  
Nicotinic Acetylcholine

α-Conotoxin GeXIVA[1,2] is a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype. It has the advantages of strong efficacy, no tolerance, and no effect on motor function, which has been expected help patients with neuropathic pain. However, drug development for clinical use is severely limited owing to its instability. Lyophilization is applied as the most preferred method to solve this problem. The prepared lyophilized powder is characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR). Molecular simulation is also used to explore the internal distribution and forces formed in the system. The analgesic effect on paclitaxel-induced neuropathic pain following single and 14-day repeated administrations are evaluated by the von Frey test and the tail-flick test. Trehalose combined with mannitol in a ratio of 1:1 is employed as the excipients in the determined formulation, where trehalose acts as the stabilizer and mannitol acts as the bulking agent, according to the results of DSC, PXRD, and FTIR. Both GeXIVA[1,2] (API) and GeXIVA[1,2] lyophilized powder (formulation) could produce stable analgesic effect. These results indicated that GeXIVA[1,2] lyophilized powder could improve the stability and provide an effective strategy to push it into clinical use as a new analgesic drug.

scholarly journals JI017 Attenuates Oxaliplatin-Induced Cold Allodynia via Spinal TRPV1 and Astrocytes Inhibition in Mice

2021 ◽  
Vol 22 (16) ◽  
pp. 8811
Author(s):  
Ji Hwan Lee ◽  
Hyunseung Ji ◽  
Seong-Gyu Ko ◽  
Woojin Kim
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Zingiber Officinale ◽  
Pcr Analysis ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 μg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.

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