Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.
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.
Gavva
Narender R
NR
Department of Neuroscience, MS 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. ngavva@amgen.com
Treanor
James J S
JJ
Garami
Andras
A
Fang
Liang
L
Surapaneni
Sekhar
S
Akrami
Anna
A
Alvarez
Francisco
F
Bak
Annette
A
Darling
Mary
M
Gore
Anu
A
Jang
Graham R
GR
Kesslak
James P
JP
Ni
Liyun
L
Norman
Mark H
MH
Palluconi
Gabrielle
G
Rose
Mark J
MJ
Salfi
Margaret
M
Tan
Edward
E
Romanovsky
Andrej A
AA
Banfield
Christopher
C
Davar
Gudarz
G
D000328:Adult; D000818:Animals; D052160:Benzothiazoles / Q000009:adverse effects* / Q000494:pharmacology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005334:Fever / Q000139:chemically induced* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*
D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human