Use of Sensory Methods for Detecting Target Engagement in Clinical Trials of New Analgesics

Chizh, Boris A.; Sang, Christine N.

doi:10.1016/j.nurt.2009.08.005

Cited by 14 publications

(10 citation statements)

References 39 publications

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“…The inter-arm reproducibility ( Figure 2B) was completed in 10 healthy Caucasian volunteers, of which six were males. Mean ± SD (range) for age, BMI, systolic blood pressure, diastolic blood pressure and heart rate were 23 ± 2 (19)(20)(21)(22)(23)(24)(25) years, 21 ± 3 (19-25) kg m À2 , 119 ± 13 (99-138) mmHg, 73 ± 7 (63-82) mmHg and 76 ± 9 (63-93) bpm, respectively. There was no difference in DBF response to 10% CA between the right and left arms at 10 min (1087 ± 372 vs. 1009 ± 349%, P = 0.60), 20 min (1181 ± 405 vs. 1236 ± 363%, P = 0.80), 30 min (1084 ± 401 vs. 1135 ± 365%, P = 0.91), 40 min (921 ± 418 vs. 992 ± 414%, P = 0.44), and 50 min (642 ± 356 vs. 686 ± 346%, P = 0.26) (paired t-test).…”

Section: Resultsmentioning

confidence: 99%

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Buntinx

Chang

Amin

et al. 2016

Brit J Clinical Pharma

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AIMTo develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODSDose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTSAll three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC 0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC 0-50min , CCC = 0.91) and visits (AUC 0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONSEvaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cinnamaldehyde, the main component of cinnamon, activates the TRPA1 receptor and induces vasodilatation when applied on the human skin.• TRPA1, a non-selective cation channel, is expressed in small diameter nociceptors and involved in persistent to chronic painful states such as inflammation, neuropathic pain and migraine.• TRPA1 is an emerging target for treating these and other neurogenic inflammatory conditions. WHAT THIS STUDY ADDS• Cinnamaldehyde 10% topical solution is tolerable and safe to use in healthy volunteers.• Cinnamaldehyde 10% applied on the human skin induces a robust increase in dermal blood flow which can be measured with laser Doppler imaging and is reproducible over time and between arms. • The cinnamaldehyde model can be used in future early clinical development studies with TRPA1 antagonists as a target engagement biomarker to guide dose selections for efficacy studies. Tables of Links

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Section: Resultsmentioning

confidence: 99%

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Buntinx

Chang

Amin

et al. 2016

Brit J Clinical Pharma

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“…SB 705498 also appears to be devoid of hyperthermia issues and is rapidly absorbed with a long elimination half-life of 50-60 h (Chizh and Sang 2009). The study used both capsaicin cough challenge and 24-h ambulatory cough monitoring.…”

Section: Trpv1 Antagonists In the Clinicmentioning

confidence: 99%

Targeting TRP channels for chronic cough: from bench to bedside

Bonvini

Birrell

Smith

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Cough is currently the most common reason for patients to visit a primary care physician in the UK, yet it remains an unmet medical need. Current therapies have limited efficacy or have potentially dangerous side effects. Under normal circumstances, cough is a protective reflex to clear the lungs of harmful particles; however, in disease, cough can become excessive, dramatically impacting patients' lives. In many cases, this condition is linked to inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD), but can also be refractory to treatment and idiopathic in nature. Therefore, there is an urgent need to develop therapies, and targeting the sensory afferent arm of the reflex which initiates the cough reflex may uncover novel therapeutic targets. The cough reflex is initiated following activation of ion channels present on vagal sensory afferents. These ion channels include the transient receptor potential (TRP) family of cation-selective ion channels which act as cellular sensors and respond to changes in the external environment. Many direct activators of TRP channels, including arachidonic acid derivatives, a lowered airway pH, changes in temperature, and altered airway osmolarity are present in the diseased airway where responses to challenge agents which activate airway sensory nerve activity are known to be enhanced. Furthermore, the expression of some TRP channels is increased in airway disease. Together, this makes them promising targets for the treatment of chronic cough. This review will cover the current understanding of the role of the TRP family of ion channels in the activation of airway sensory nerves and cough, focusing on four members, transient receptor potential vanilloid (TRPV) 1, transient receptor potential ankyrin (TRPA) 1, TRPV4, and transient receptor potential melastatin (TRPM) 8 as these represent the channels where most information has been gathered with relevance to the airways. We will describe recent data and highlight the possible therapeutic utility of specific TRP channel antagonists as antitussives in the clinic.

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“…For example, the TRPV1 receptor is responsible for a burning pain sensation and can be activated using, for example, capsaicin. TRPV1 antagonists can be tested in an experimental model of capsaicin-induced burning pain and hypersensitivity [42].…”

Section: Mechanical Stimulationmentioning

confidence: 99%

Translational pain biomarkers in the early development of new neurotherapeutics for pain management

Arendt‐Nielsen

Nielsen

Gazerani

2014

Expert Review of Neurotherapeutics

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Translation of the analgesic efficacy of investigational neurotherapeutics from pre-clinical pain models into clinical trial phases is associated with a high risk of failure. Application of human pain biomarkers in early stages of clinical trials can potentially enhance the rate of successful translation, which would eventually reduce both length and costs of drug development after the pre-clinical stage. Human pain biomarkers are based on the standardized activation of pain pathways followed by the assessment of ongoing and paroxysmal pain, plus evoked responses which can be applied to healthy individuals and patients prior to and after pharmacological interventions. This review discusses the rationality and feasibility of advanced human pain biomarkers in early phases of drug development for pain management which is still an unmet medical need.

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Use of Sensory Methods for Detecting Target Engagement in Clinical Trials of New Analgesics

Cited by 14 publications

References 39 publications

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Targeting TRP channels for chronic cough: from bench to bedside

Translational pain biomarkers in the early development of new neurotherapeutics for pain management

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