Published Online, 13 September 2005, www.theannals.com, DOI 10.1345/aph.1E572.
The Annals of Pharmacotherapy: Vol. 39, No. 10, pp. 1693-1699. DOI 10.1345/aph.1E572
© 2005 Harvey Whitney Books Company.
NEW DRUG DEVELOPMENTS
Ruboxistaurin, a Protein Kinase C ß Inhibitor, as an Emerging Treatment for Diabetes Microvascular Complications
Scott V Joy, MD CDE FACP1,
Ann C Scates, PharmD2,
Srilaxmi Bearelly, MD3,
Moahad Dar, MD4,
Christina A Taulien, MD5,
Jason A Goebel, MD6, and
Michael J Cooney, MD7
1 Associate Clinical Professor of Medicine, Department of Medicine, Duke
University Medical Center, Durham, NC
2 Clinical Pharmacist and Drug Information Specialist, Department of Pharmacy,
Duke University Hospital
3 Assistant Professor of Ophthalmology, Department of Ophthalmology, Duke
University Medical Center
4 Fellow in Endocrinology, Department of Medicine, Duke University Medical
Center
5 Resident in Internal Medicine, Department of Medicine, Duke University Medical
Center
6 Resident in Internal Medicine, Department of Medicine, Duke University Medical
Center
7 Assistant Professor of Ophthalmology, Department of Ophthalmology, Duke
University Medical Center
Reprints: Dr. Joy, Department of Medicine, Duke University Medical
Center, 3024 Pickett Rd., Durham, NC 27705-0493, fax 919/419-5842,
joy00002{at}mc.duke.edu
OBJECTIVE: To review current clinical data regarding the
pharmacologic actions of ruboxistaurin (LY333531) mesylate, an inhibitor of
protein kinase C (PKC) ß, and its role to potentially reduce the
development and/or the progression of diabetic microvascular
complications.
DATA SOURCES: Primary literature was obtained via a MEDLINE search
(1966-August 2004) and through review of pertinent abstracts and presentations
at major medical meetings.
STUDY SELECTION AND DATA EXTRACTION: Literature relevant to PKC
physiology, the pharmacokinetics of ruboxistaurin, and data evaluating the use
of ruboxistaurin in treating diabetic microvascular complications in human and
relevant animal models was reviewed.
DATA SYNTHESIS: PKC is part of a group of intracellular signaling
molecules activated in response to various specific hormonal, neuronal, and
growth factor stimuli. Hyperglycemia leads to PKC ß 1 and 2 isoform
activation, which experimentally has been shown to contribute to the
development and progression of diabetic microvascular complications
(retinopathy, nephropathy, neuropathy) through various biochemical mechanisms.
Animal and/or human studies using ruboxistaurin mesylate, a novel, highly
selective inhibitor of PKC ß, have shown delay in the progression and, in
some cases, reversal of diabetic retinopathy, nephropathy, and neuropathy.
CONCLUSIONS: Ruboxistaurin mesylate, by inhibiting excessive
activation of certain PKC isoforms, has the potential to reduce the burden of
microvascular complications for patients with diabetes.
Key Words: diabetic microvascular complications, LY333531, protein kinase C, ruboxistaurin
Published Online, September 13, 2005. www.theannals.com, DOI 10.1345/aph.1E572
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Copyright © 2005 by Harvey Whitney Books Company.
