PMID- 25052834
OWN - NLM
STAT- MEDLINE
DCOM- 20141125
LR  - 20231104
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 351
IP  - 1
DP  - 2014 Oct
TI  - Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic 
      subjects.
PG  - 33-43
LID - 10.1124/jpet.114.215616 [doi]
AB  - Although resistance to the P2Y12 antagonist clopidogrel is linked to altered drug 
      metabolism, some studies suggest that these pharmacokinetic abnormalities only 
      partially account for drug resistance. To circumvent pharmacokinetic 
      complications and target P2Y12 receptor function we applied the direct P2Y12 
      antagonist 2-methylthio-AMP (2-methylthioadenosine 5'-monophosphate 
      triethylammonium salt) to purified platelets ex vivo. Platelets were purified 
      from healthy and type 2 diabetes mellitus (T2DM) patients and stimulated with 
      thrombin or the selective protease-activated receptor agonists, 
      protease-activated receptor 1-activating peptide (PAR1-AP), or PAR4-AP. Platelet 
      activation as measured by alphaIIbbeta3 activation, and P-selectin expression was 
      monitored in 141 subjects. Our results demonstrate that, compared with healthy 
      subjects, platelets from diabetic patients are resistant to inhibition by 
      2-methylthio-AMP, demonstrating P2Y12 pharmacodynamic defects among diabetic 
      patients. Inhibition of thrombin-mediated alphaIIbbeta3 activation by 2-methylthio-AMP 
      was lower in diabetic platelets versus healthy platelets. Subgroup analysis 
      revealed a racial difference in the resistance to 2-methylthio-AMP. We found no 
      resistance in platelets from diabetic African Americans; they were inhibited by 
      2-methylthio-AMP equally as well as platelets from healthy African Americans. In 
      contrast, platelets from Caucasian patients with diabetes were resistant to P2Y12 
      antagonism compared with healthy Caucasians. Multivariable analysis demonstrated 
      that other variables, such as obesity, age, or gender, could not account for the 
      differential resistance to 2-methylthio-AMP among races. These results suggest 
      that in addition to altered drug metabolism, P2Y12 receptor function itself is 
      altered in the Caucasian diabetic population. The racial difference in platelet 
      function in T2DM is a novel finding, which may lead to differences in treatment 
      as well as new targets for antiplatelet therapy.
CI  - Copyright (c) 2014 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Cleator, John H
AU  - Cleator JH
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.) john.cleator@vanderbilt.edu heidi.hamm@vanderbilt.edu.
FAU - Duvernay, Matthew T
AU  - Duvernay MT
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Holinstat, Michael
AU  - Holinstat M
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Colowick, Nancy E
AU  - Colowick NE
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Hudson, Willie J
AU  - Hudson WJ
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Song, Yanna
AU  - Song Y
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Harrell, Frank E
AU  - Harrell FE
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.).
FAU - Hamm, Heidi E
AU  - Hamm HE
AD  - Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), 
      Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and 
      Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, 
      Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for 
      Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 
      (M.H.) john.cleator@vanderbilt.edu heidi.hamm@vanderbilt.edu.
LA  - eng
GR  - R00 HL089457/HL/NHLBI NIH HHS/United States
GR  - R00-HL089457/HL/NHLBI NIH HHS/United States
GR  - UL1-RR024975/RR/NCRR NIH HHS/United States
GR  - P50-HL081009/HL/NHLBI NIH HHS/United States
GR  - UL1 RR024975/RR/NCRR NIH HHS/United States
GR  - P50 HL081009/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140722
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (2-methylthioadenosine 5'-monophosphate)
RN  - 0 (Purinergic P2Y Receptor Antagonists)
RN  - 415SHH325A (Adenosine Monophosphate)
SB  - IM
MH  - Adenosine Monophosphate/*analogs & derivatives/pharmacokinetics/*pharmacology
MH  - Adult
MH  - Black or African American
MH  - Blood Platelets/*drug effects
MH  - Diabetes Mellitus, Type 2/*ethnology/metabolism
MH  - *Drug Resistance
MH  - Female
MH  - Humans
MH  - Male
MH  - Purinergic P2Y Receptor Antagonists/*pharmacology
MH  - White People
PMC - PMC4165026
EDAT- 2014/07/24 06:00
MHDA- 2014/12/15 06:00
PMCR- 2015/10/01
CRDT- 2014/07/24 06:00
PHST- 2014/07/24 06:00 [entrez]
PHST- 2014/07/24 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - jpet.114.215616 [pii]
AID - JPET_215616 [pii]
AID - 10.1124/jpet.114.215616 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2014 Oct;351(1):33-43. doi: 10.1124/jpet.114.215616. Epub 
      2014 Jul 22.