title: The new oral immunomodulating drug DiNAC induces brachial artery vasodilatation at rest and during hyperemia in hypercholesterolemic subjects, likely by a nitric oxide-dependent mechanism.
abstract: OBJECTIVE
  To investigate if the immunomodulator drug DINAC (1) affects arterial dimensions in asymptomatic patients with hypercholesterolemia, (2) has effects on leucocyte markers of inflammation and (3) has in vitro effects on nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC).
  
  
  RESULTS
  One hundred and fifty-three patients with asymptomatic hypercholesterolemia were randomized to either 100 or 500 mg of DINAC or placebo in a double-blind, parallel-group fashion for 24 weeks. Treatment at the highest dose induced a significant increase in resting brachial artery diameter measured by ultrasound and also induced a significant increase in vessel diameter during hyperemia. However, flow-mediated vasodilation (FMD) and the vasodilatory response to nitroglycerin, lipid levels or leukocyte count were unaltered. Expression of several cell surface markers of inflammation, like CD11b and CD25, were reduced by treatment. In vitro, DINAC counteracted TNF-alpha induced reductions in NO levels and in NOS protein and mRNA levels.
  
  
  CONCLUSIONS
  The immunomodulator drug DINAC increased brachial artery diameter at rest and during hyperemia in asymptomatic subjects with hypercholesterolemia without affecting blood lipid levels. Based on parallel in vitro studies this effect is likely due to an enhancement of NOS activity.
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Knut
authors.initials: K
authors.lastname: Pettersson
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Kjerrulf
authors.affiliation: Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Jungersten
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Kicki
authors.initials: K
authors.lastname: Johansson
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Långström
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Inge
authors.initials: I
authors.lastname: Kalies
authors.affiliation: Capio Diagnostik/CALAB Research, Flow Cytometry Laboratory, Stockholm, Sweden.
authors.forename: Rodica
authors.initials: R
authors.lastname: Lenkei
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Walldius
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden; Department of Medicine, University Hospital, Uppsala, Sweden. Electronic address: lars.lind@medsci.uu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000368:Aged; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects; D002478:Cells, Cultured; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D006940:Hyperemia / Q000188:drug therapy; D007155:Immunologic Factors / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects; D017698:Postmenopause; D014463:Ultrasonography; D014471:Umbilical Veins / Q000166:cytology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D007155:Immunologic Factors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D003553:Cystine; C056709:N,N-diacetylcystine; D052250:Nitric Oxide Synthase Type III; D000111:Acetylcysteine