The effect of a prostaglandin DP-receptor partial agonist (192C86) on platelet aggregation and the cardiovascular system in healthy volunteers.
1. PGD2 (DP)-receptors mediate inhibition of platelet aggregation and vasodilatation. If receptor reserve were greater on platelets it might be possible to separate these effects. To determine whether such a difference in receptor reserve exists, we have examined the effects of a highly selective DP-receptor partial agonist 192C86 on platelet aggregation and the cardiovascular system in healthy volunteers. 2. Using an open, dose-escalating study design, four male volunteers received constant rate intravenous infusions of 192C86 for up to 60 min. Ex vivo platelet aggregation to ADP and collagen in platelet-rich plasma (PRP) and whole blood (WB) was studied at baseline, after 15, 30 and 60 min of each infusion and at 180 min post-infusion. Heart rate (HR), systolic and diastolic (DBP) blood pressure were measured at frequent intervals. Adverse experiences were monitored by checklist. Facial flushing was assessed by the volunteer using a visual analogue scale, by an observer using a numerical scale and by full-face colour photographs. Blood was taken for assay of plasma 192C86 concentrations by radio-immunoassay (r.i.a.). 3. 192C86 (0.007-0.058 micrograms kg-1 min-1) inhibited platelet aggregation to ADP and collagen both in PRP and WB in a dose-dependent manner. However, this was always accompanied by a decrease in DBP, increase in HR and facial flushing. Plasma concentrations of 192C86 were at or below the limits of sensitivity of the r.i.a. (0.5 ng ml-1). 4. The highest infusion rate was stopped after 20 min due to symptomatic hypotension on standing.(ABSTRACT TRUNCATED AT 250 WORDS)
Gray
S J
SJ
Department of Clinical Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Giles
H
H
Posner
J
J
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002087:Butyrates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005483:Flushing / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000187:drug effects*
D002087:Butyrates; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C078640:4-((1-((2-cyclohexyl-2-hydroxyethylidene)amino)-3-ethyloctahydro-2-oxo-5-cyclopentimidazolyl)thio)butanoic acid; C036293:prostaglandin D2 receptor