A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain

Ziegler, Dan; Duan, W. Rachel; An, Guohua; Thomas, James S.; Nothaft, Wolfram

doi:10.1097/j.pain.0000000000000263

Cited by 81 publications

(53 citation statements)

References 20 publications

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“…However, subsequent clinical trials of ABT-639 with human volunteers showed no effect in an acute intradermal capsaicin pain model in which pregabalin was effective 192 . Similarly, ABT-639 did not reduce pain in patients with diabetic neuropathy 193 . Other Cav3.2 inhibitors have been described to be effective in pain models, including a rat model of pain from irritable bowel syndrome.…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 89%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

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Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

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Section: Ion Channels As Drug Targetsmentioning

confidence: 89%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

View full text Add to dashboard Cite

show abstract

“…Furthermore, we are aware of at least two T-type channel blockers that are being tested in humans for safety and efficacy in pain: Z944 (Lee, 2014) and 4,6,7,8,pyrazine-2-carbonyl]-4-chloro-2-fluoro-N-(2-fluorophenyl) benzenesulfonamide] (Ziegler et al, 2015). This underscores the importance of T-type calcium channels (particularly Ca V 3.2) in the primary afferent pain pathway.…”

Section: Ca V 3 Channel Pathophysiologymentioning

confidence: 99%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

903

992

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“…; Ziegler et al . ). Here, we conducted a comprehensive characterization of T‐channel function in the mouse and rat subiculum by combining whole‐cell patch‐clamp electrophysiology with pharmacological, molecular and genetic tools that selectively target T‐channels.…”

Section: Introductionmentioning

confidence: 99%

The role of T‐type calcium channels in the subiculum: to burst or not to burst?

Joksimović

Eggan

Izumi³

et al. 2017

The Journal of Physiology

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Several studies suggest that voltage-gated calcium currents are involved in generating high frequency burst firing in the subiculum, but the exact nature of these currents remains unknown. Here, we used selective pharmacology, molecular and genetic approaches to implicate Cav3.1-containing T-channels in subicular burst firing, in contrast to several previous reports discounting T-channels as major contributors to subicular neuron physiology. Furthermore, pharmacological antagonism of T-channels, as well as global deletion of CaV3.1 isoform, completely suppressed development of long-term potentiation (LTP) in the CA1-subiculum, but not in the CA3-CA1 pathway. Our results indicate that excitability and synaptic plasticity of subicular neurons relies heavily on T-channels. Hence, T-channels may be a promising new drug target for different cognitive deficits.

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A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain

Abstract: Supplemental Digital Content is Available in the Text.Treatment with ABT-639 100 mg for 6 weeks did not significantly reduce pain in patients with diabetic peripheral neuropathy.

Cited by 81 publications

References 20 publications

Breaking barriers to novel analgesic drug development

Breaking barriers to novel analgesic drug development

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

The role of T‐type calcium channels in the subiculum: to burst or not to burst?

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