![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 290, Issue 2, 551-560, August 1999
Departments of Pharmacology, Biochemistry and Molecular Biology,
and Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
Kirkland, Quebec, Canada (C.-C.C., C.B., S.C., W.C., D.E., J.E.,
A.W.F.-H., J.Y.G., R.G., M.G., J.G., S.K., B.K., Y.L., S.L., J.M.,
G.P.O., M.O., M.D.P., H.P., P.P., I.R., P.T., M.T., P.V., Z.W., E.W.,
L.-J.X., R.N.Y., R.Z., D.R.); Department of Pharmacology, Merck
Research Laboratories, Harlow, UK (S.B., J.W.); Department of
Pharmacology, Merck Research Laboratories, Rahway, New Jersey (M.J.F.,
D.V.); and Safety Assessment, Merck Research Laboratories, West Point,
Pennsylvania (D.P.)
The discoveries that cyclooxygenase (COX)-2 is an inducible form
of COX involved in inflammation and that COX-1 is the major isoform
responsible for the production of prostaglandins (PGs) in the
gastrointestinal tract have provided a rationale for the development of
specific COX-2 inhibitors as a new class of anti-inflammatory agents
with improved gastrointestinal tolerability. In the present study, the
preclinical pharmacological and biochemical profiles of rofecoxib
[Vioxx, also known as MK-0966,
4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent
inhibitor of the COX-2-dependent production of PGE2 in human osteosarcoma cells (IC50 = 26 ± 10 nM) and
Chinese hamster ovary cells expressing human COX-2
(IC50 = 18 ± 7 nM) with a 1000-fold selectivity
for the inhibition of COX-2 compared with the inhibition of COX-1
activity (IC50 > 50 µM in U937 cells and
IC50 > 15 µM in Chinese hamster ovary cells
expressing human COX-1). Rofecoxib is a time-dependent inhibitor of
purified human recombinant COX-2 (IC50 = 0.34 µM)
but caused inhibition of purified human COX-1 in a non-time-dependent
manner that could only be observed at a very low substrate
concentration (IC50 = 26 µM at 0.1 µM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE2 synthesis with an IC50 value of 0.53 ± 0.02 µM compared with an IC50 value of 18.8 ± 0.9 µM for the inhibition of COX-1-derived thromboxane B2
synthesis after blood coagulation. Using the ratio of the COX-1
IC50 values over the COX-2 IC50 values in the
human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in
vivo rodent models, rofecoxib is a potent inhibitor of
carrageenan-induced paw edema (ID50 = 1.5 mg/kg),
carrageenan-induced paw hyperalgesia (ID50 = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID50 = 0.24 mg/kg), and adjuvant-induced arthritis (ID50 = 0.74 mg/kg/day). Rofecoxib also has a protective effect on
adjuvant-induced destruction of cartilage and bone structures in rats.
In a 51Cr excretion assay for detection of gastrointestinal
integrity in either rats or squirrel monkeys, rofecoxib has no effect
at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and
represents a new therapeutic class of anti-inflammatory agents for the
treatment of the symptoms of osteoarthritis and rheumatoid arthritis
with improved gastrointestinal tolerability.
This article has been cited by other articles:
|
|
 |
|
  M. A. F. de Godoy, N. Rattan, and S. Rattan Arachidonic acid metabolites follow the preferential course of cyclooxygenase pathway for the basal tone in the internal anal sphincter Am J Physiol Gastrointest Liver Physiol, April 1, 2009; 296(4): G727 - G734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. F. de Godoy, N. Rattan, and S. Rattan COX-1 vs. COX-2 as a determinant of basal tone in the internal anal sphincter Am J Physiol Gastrointest Liver Physiol, February 1, 2009; 296(2): G219 - G225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Hegen, J C Keith Jr, M Collins, and C L Nickerson-Nutter Utility of animal models for identification of potential therapeutics for rheumatoid arthritis Ann Rheum Dis, November 1, 2008; 67(11): 1505 - 1515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Clark, S. E. Rowland, D. Denis, M.-C. Mathieu, R. Stocco, H. Poirier, J. Burch, Y. Han, L. Audoly, A. G. Therien, et al. MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 425 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-S. Bhat, S. Kumar Tandan, D. Kumar, V. Krishna, and V. R. Prakash The Interaction Between Inhibitors of Nitric Oxide Synthase and Cyclooxygenase in Formalin-Induced Pain in Mice: An Isobolographic Study Anesth. Analg., March 1, 2008; 106(3): 978 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pyrko, A. Kardosh, Y.-T. Liu, N. Soriano, W. Xiong, R. H. Chow, J. Uddin, N. A. Petasis, A. K. Mircheff, R. A. Farley, et al. Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib Mol. Cancer Ther., April 1, 2007; 6(4): 1262 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Matson, D. C. Broom, S. R. Carson, J. Baldassari, J. Kehne, and D. N. Cortright Inflammation-Induced Reduction of Spontaneous Activity by Adjuvant: A Novel Model to Study the Effect of Analgesics in Rats J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 194 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Hewett, J. M. Silakova, and J. A. Hewett Oral Treatment with Rofecoxib Reduces Hippocampal Excitotoxic Neurodegeneration J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1219 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Schmelzer, B. Inceoglu, L. Kubala, I.-H. Kim, S. L. Jinks, J. P. Eiserich, and B. D. Hammock Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors PNAS, September 12, 2006; 103(37): 13646 - 13651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Kroin, A. Buvanendran, D. E. Watts, C. Saha, and K. J. Tuman Upregulation of cerebrospinal fluid and peripheral prostaglandin E2 in a rat postoperative pain model. Anesth. Analg., August 1, 2006; 103(2): 334 - 43, table of contents. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Medicherla, J. Y. Ma, R. Mangadu, Y. Jiang, J. J. Zhao, R. Almirez, I. Kerr, E. G. Stebbins, G. O'Young, A. M. Kapoun, et al. A Selective p38{alpha} Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 132 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmassmann, G. Zoidl, B. M. Peskar, B. Waser, D. Schmassmann-Suhijar, J.-O. Gebbers, and J. C. Reubi Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice Am J Physiol Gastrointest Liver Physiol, April 1, 2006; 290(4): G747 - G756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Schimizzi, A. A. Jamali, K. D. Herbst, and R. A. Pedowitz Acute Compartment Syndrome Due to Ruptured Baker Cyst After Nonsurgical Management of an Anterior Cruciate Ligament Tear: A Case Report Am. J. Sports Med., April 1, 2006; 34(4): 657 - 660. [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Welsh, C. M. Mitchell, W. A. Walters, S. Mesiano, and T. Zakar Prostaglandin H2 synthase-1 and -2 expression in guinea pig gestational tissues during late pregnancy and parturition J. Physiol., December 15, 2005; 569(3): 903 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Corazzi, M. Leone, R. Maucci, L. Corazzi, and P. Gresele Direct and Irreversible Inhibition of Cyclooxygenase-1 by Nitroaspirin (NCX 4016) J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1331 - 1337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fosslien Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 347 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Zatelli, A. Luchin, D. Piccin, F. Tagliati, A. Bottoni, C. Vignali, M. Bondanelli, and E. C. degli Uberti Cyclooxygenase-2 Inhibitors Reverse Chemoresistance Phenotype in Medullary Thyroid Carcinoma by a Permeability Glycoprotein-Mediated Mechanism J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5754 - 5760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. H. Huntjens, M. Danhof, and O. E. Della Pasqua Pharmacokinetic pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors Rheumatology, July 1, 2005; 44(7): 846 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mollace, C. Muscoli, E. Masini, S. Cuzzocrea, and D. Salvemini Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors Pharmacol. Rev., June 1, 2005; 57(2): 217 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Fredy, D. A Diggins Jr, and G. B Morrill Blood Pressure in Native Americans Switched from Celecoxib to Rofecoxib Ann. Pharmacother., May 1, 2005; 39(5): 797 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steffel, M. Hermann, H. Greutert, S. Gay, T. F. Luscher, F. Ruschitzka, and F. C. Tanner Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation Circulation, April 5, 2005; 111(13): 1685 - 1689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Gierse, Y. Zhang, W. F. Hood, M. C. Walker, J. S. Trigg, T. J. Maziasz, C. M. Koboldt, J. L. Muhammad, B. S. Zweifel, J. L. Masferrer, et al. Valdecoxib: Assessment of Cyclooxygenase-2 Potency and Selectivity J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1206 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Puhlmann, C. Ziemann, G. Ruedell, H. Vorwerk, D. Schaefer, C. Langebrake, P. Schuermann, U. Creutzig, and D. Reinhardt Impact of the Cyclooxygenase System on Doxorubicin-Induced Functional Multidrug Resistance 1 Overexpression and Doxorubicin Sensitivity in Acute Myeloid Leukemic HL-60 Cells J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Harris, L. Black, S. Surapaneni, T. Kolasa, S. Majest, M. T. Namovic, G. Grayson, V. Komater, D. Wilcox, L. King, et al. ABT-963 [2-(3,4-Difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], A Highly Potent and Selective Disubstituted Pyridazinone Cyclooxgenase-2 Inhibitor J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 904 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Simmons, R. M. Botting, and T. Hla Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition Pharmacol. Rev., September 1, 2004; 56(3): 387 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Hegi, T. Bombeli, B. Seifert, P. C. Baumann, U. Haller, M. P. Zalunardo, T. Pasch, and D. R. Spahn Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac Br. J. Anaesth., April 1, 2004; 92(4): 523 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Blaicher, H. T. Landsteiner, O. Al-Falaki, J. Zwerina, I. Volf, D. Gruber, M. Zimpfer, and K. Hoerauf Acetylsalicylic Acid, Diclofenac, and Lornoxicam, but Not Rofecoxib, Affect Platelet CD 62 Expression Anesth. Analg., April 1, 2004; 98(4): 1082 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K Sandhu and C. A Heyneman Nephrotoxic Potential of Selective Cyclooxygenase-2 Inhibitors Ann. Pharmacother., April 1, 2004; 38(4): 700 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Higuchi, T. Iwama, K. Yoshinaga, M. Toyooka, M. M. Taketo, and K. Sugihara A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Rofecoxib, a Selective Cyclooxygenase-2 Inhibitor, on Rectal Polyps in Familial Adenomatous Polyposis Patients Clin. Cancer Res., October 15, 2003; 9(13): 4756 - 4760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B J R Whittle New dogmas or old? Gut, September 1, 2003; 52(9): 1379 - 1381. [Abstract] [Full Text]
|
|
|
|
|
|
B. M. Peskar, N. Sawka, K. Ehrlich, and B. A. Peskar Role of Cyclooxygenase-1 and -2, Phospholipase C, and Protein Kinase C in Prostaglandin-Mediated Gastroprotection J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1233 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Gajraj Cyclooxygenase-2 Inhibitors Anesth. Analg., June 1, 2003; 96(6): 1720 - 1738. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Y. Zhang, J. Zhan, C. S. Cook, R. M. Ings, and A. P. Breau Involvement of Human UGT2B7 and 2B15 in Rofecoxib Metabolism Drug Metab. Dispos., May 1, 2003; 31(5): 652 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Claveau, M. Sirinyan, J. Guay, R. Gordon, C.-C. Chan, Y. Bureau, D. Riendeau, and J. A. Mancini Microsomal Prostaglandin E Synthase-1 Is a Major Terminal Synthase That Is Selectively Up-Regulated During Cyclooxygenase-2-Dependent Prostaglandin E2 Production in the Rat Adjuvant-Induced Arthritis Model J. Immunol., May 1, 2003; 170(9): 4738 - 4744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Callejas, A. Fernandez-Martinez, A. Castrillo, L. Bosca, and P. Martin-Sanz Selective Inhibitors of Cyclooxygenase-2 Delay the Activation of Nuclear Factor kappa B and Attenuate the Expression of Inflammatory Genes in Murine Macrophages Treated with Lipopolysaccharide Mol. Pharmacol., March 1, 2003; 63(3): 671 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kitahara, F. Eitner, T. Ostendorf, U. Kunter, U. Janssen, R. Westenfeld, K. Matsui, D. Kerjaschki, and J. Floege Selective Cyclooxygenase-2 Inhibition Impairs Glomerular Capillary Healing in Experimental Glomerulonephritis J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1261 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Leahy, R. L. Ornberg, Y. Wang, B. S. Zweifel, A. T. Koki, and J. L. Masferrer Cyclooxygenase-2 Inhibition by Celecoxib Reduces Proliferation and Induces Apoptosis in Angiogenic Endothelial Cells in Vivo Cancer Res., February 1, 2002; 62(3): 625 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Hill Substance P, opioid, and catecholamine systems in the mouse central nervous system (CNS) PNAS, January 22, 2002; 99(2): 549 - 551. [Full Text] [PDF]
|
|
|
|
|
|
F HALTER, A S TARNAWSKI, A SCHMASSMANN, and B M PESKAR Cyclooxygenase 2{---}implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives Gut, September 1, 2001; 49(3): 443 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. FitzGerald and C. Patrono The Coxibs, Selective Inhibitors of Cyclooxygenase-2 N. Engl. J. Med., August 9, 2001; 345(6): 433 - 442. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pall, B. E. Friden, and M. Brannstrom Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study Hum. Reprod., July 1, 2001; 16(7): 1323 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Riendeau, M. D. Percival, C. Brideau, S. Charleson, D. Dubé, D. Ethier, J.-P. Falgueyret, R. W. Friesen, R. Gordon, G. Greig, et al. Etoricoxib (MK-0663): Preclinical Profile and Comparison with Other Agents That Selectively Inhibit Cyclooxygenase-2 J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 558 - 566. [Abstract] [Full Text]
|
|
|
|
 |
|
 I. A. Mardini and G. A. FitzGerald Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs Mol. Interv., April 1, 2001; 1(1): 30 - 38. [Abstract] [Full Text]
|
|
|
|
|
|
M. Oshima, N. Murai, S. Kargman, M. Arguello, P. Luk, E. Kwong, M. M. Taketo, and J. F. Evans Chemoprevention of Intestinal Polyposis in the Apc{{Delta}}716 Mouse by Rofecoxib, a Specific Cyclooxygenase-2 Inhibitor Cancer Res., February 1, 2001; 61(4): 1733 - 1740. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Saag, D. van der Heijde, C. Fisher, A. Samara, L. DeTora, J. Bolognese, R. Sperling, B. Daniels, and for the Osteoarthritis Studies Group Rofecoxib, a New Cyclooxygenase 2 Inhibitor, Shows Sustained Efficacy, Comparable With Other Nonsteroidal Anti-inflammatory Drugs: A 6-Week and a 1-Year Trial in Patients With Osteoarthritis Arch Fam Med, November 1, 2000; 9(10): 1124 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Halpin, L. A. Geer, K. E. Zhang, T. M. Marks, D. C. Dean, A. N. Jones, D. Melillo, G. Doss, and K. P. Vyas The Absorption, Distribution, Metabolism and Excretion of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Rats and Dogs Drug Metab. Dispos., October 1, 2000; 28(10): 1244 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G Sigthorsson, R Crane, T Simon, M Hoover, H Quan, J Bolognese, and I Bjarnason COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin Gut, October 1, 2000; 47(4): 527 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Grubbs, R. A. Lubet, A. T. Koki, K. M. Leahy, J. L. Masferrer, V. E. Steele, G. J. Kelloff, D. L. Hill, and K. Seibert Celecoxib Inhibits N-Butyl-N-(4-hydroxybutyl)-nitrosamine-induced Urinary Bladder Cancers in Male B6D2F1 Mice and Female Fischer-344 Rats Cancer Res., October 1, 2000; 60(20): 5599 - 5602. [Abstract] [Full Text]
|
|
|
|
|
|
B J R WHITTLE COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors Gut, September 1, 2000; 47(3): 320 - 325. [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Mancini, K. Blood, J. Guay, R. Gordon, D. Claveau, C.-C. Chan, and D. Riendeau Cloning, Expression, and Up-regulation of Inducible Rat Prostaglandin E Synthase during Lipopolysaccharide-induced Pyresis and Adjuvant-induced Arthritis J. Biol. Chem., February 2, 2001; 276(6): 4469 - 4475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Burleigh, V. R. Babaev, J. A. Oates, R. C. Harris, S. Gautam, D. Riendeau, L. J. Marnett, J. D. Morrow, S. Fazio, and M. F. Linton Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Circulation, April 16, 2002; 105(15): 1816 - 1823. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
