The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans
Abstract
The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with maximal body temperature surpassing 40 degrees C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517-induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1-selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.
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Cites
Molecular mechanisms of nociception
Julius, D., & Basbaum, A. I. (2001) · Nature · doi:10.1038/35093019 · Cited by 2,685 · cited 1×
“7), capsaicin, resiniferatoxin, components of the ‘‘inflammatory soup,” products of lipoxygenase, and G-protein coupled receptor signaling, making it a molecular integrator of pain transduction [1,14,17,29].”
BackgroundThermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system
Romanovsky, A. A. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00668.2006 · Cited by 786
Self-citationRomanovsky, A. A., Ivanov, A. I., & Shimansky, Y. P. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01173.2001 · Cited by 351
Self-citationGavva, N. R., Bannon, A. W., Hovland, D. N., Lehto, S. G., Klionsky, L., Surapaneni, S., Immke, D. C., Henley, C., Arik, L., Bak, A., et al. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.125674 · Cited by 180
Self-citationRomanovsky, A. A., Sugimoto, N., Simons, C. T., & Hunter, W. S. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00757.2002 · Cited by 68
Cited by
Skin temperature: its role in thermoregulation
Romanovsky, A. A. (2014) · Acta Physiologica · doi:10.1111/apha.12231 · Cited by 518
Self-citationThe thermo‐TRP ion channel family: properties and therapeutic implications
Vay, L., Gu, C., & McNaughton, P. A. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01601.x · Cited by 296
The cannabinoid system and pain
Woodhams, S. G., Chapman, V., Finn, D. P., Hohmann, A. G., & Neugebauer, V. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.06.015 · Cited by 267
The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not
Romanovsky, A. A., Almeida, M. C., Garami, A., Steiner, A. A., Norman, M. H., Morrison, S. F., Nakamura, K., Burmeister, J. J., & Nucci, T. B. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001263 · Cited by 253
Self-citationThe thermoregulation system and how it works
(2018) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-63912-7.00001-1 · Cited by 186
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Metadata
- Authors
- Gavva, N. R., Treanor, J. J. S., Garami, A., Fang, L., Surapaneni, S., Akrami, A., Alvarez, F., Bak, A., Darling, M., Gore, A., Jang, G. R., Kesslak, J. P., Ni, L., Norman, M. H., Palluconi, G., Rose, M. J., Salfi, M., Tan, E., Romanovsky, A. A., Banfield, C., & Davar, G.
- Venue
- Pain
- Published
- 2008-05
- Volume
- 136
- Issue
- 1
- Pages
- 202-210
- ISSN
- 0304-3959 (ISSN-L)
- OpenAlex
- W2007034094
- Cited by
- 525
- References
- 5
- FWCI
- 16.16
- Type
- journal article
- Language
- en
- Open access
- closed
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- Gavva, N. R., Treanor, J. J. S., Garami, A., Fang, L., Surapaneni, S., Akrami, A., Alvarez, F., Bak, A., Darling, M., Gore, A., Jang, G. R., Kesslak, J. P., Ni, L., Norman, M. H., Palluconi, G., Rose, M. J., Salfi, M., Tan, E., Romanovsky, A. A., . . . Davar, G. (2008). Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain. https://doi.org/10.1016/j.pain.2008.01.024
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