New Properties of Drugs are Sometimes Beneficial, Sometimes Not

New Properties of Drugs are Sometimes Beneficial, Sometimes Not

by David W. Sharp

WHAT'S HOT IN MEDICINE
Rank	Paper	Citations This Period (Sep-Oct 05)	Rank Last Period (Jul-Aug 05)
1	T.J. Lynch, et al., "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib," New Engl. J. Med., 350(21): 2129-39, 20 May 2004. [Harvard Med. Sch., Boston, MA; Harvard Sch. Public Health, Boston, MA] *821XM	102	1
2	J.G. Paez, et al., *"EGFR* mutations in lung cancer: Correlation with clinical response to gefitinib therapy,"** Science, 304(5676): 1497-1500, 4 June 2004. [7 U.S. and Japanese institutions] *825YR	90	2
3	C.P. Cannon, et al., "Intensive versus moderate lipid lowering with statins after acute coronary syndromes," New Engl. J. Med., 350(15): 1495-504, 8 April 2004. [5 institutions worldwide] *810CI	60	5
4	H.H. Hurwitz, et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer," New Engl. J. Med., 350(23): 2335-42, 3 June 2004. [9 U.S. institutions] *825JY	46	3
5	W. Pao, et al., "EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib," Proc. Natl. Acad. Sci. USA, 101(36): 13306-11, 7 September 2004. [Mem. Sloan-Kettering Cancer Ctr., New York, NY; Washington U. Sch. Med., St. Louis, MO] *853AT	42	9
6	A.A. Hedley, et al., "Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002," JAMA-J. Am. Med. Assoc., 291(23): 2847-50, 16 June 2004. [Ctrs. Dis. Control & Prevent., Atlanta, GA and Hyattsville, MD; U. Calif., Berkeley] *828GT	41	10
7	D. Cunningham, et al., "Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer," New Engl. J. Med., 351(4): 337-45, 22 July 2004. [9 institutions worldwide] *839RC	41	7
8	G.L. Anderson, et al. (Women’s Health Initiative Steering Comm.), "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial," JAMA-J. Amer. Med. Assoc., 291(14): 1701-12, 14 April 2004. [Program office: NHLBI, Bethesda, MD] *811RJ	38	4
9	P.M. Ridker, et al., "C-reactive protein levels and outcomes after statin therapy," New Engl. J. Med., 352(1): 20-8, 6 January 2005. [Brigham and Women’s Hosp., Boston, MA; Harvard Med. Sch., Boston] *884UP	37	†
10	P.E. Goss, et al., "A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer," New Engl. J. Med., 349(19): 1793-1802, 6 November 2003. [15 institutions worldwide] *739NR	36	†
SOURCE: Thomson Scientific Hot Papers Database. the Legend.

n the early days it seemed obvious. The class of drugs known as statins inhibit a key enzyme in the synthesis of cholesterol, and the benefit they provide to people with or at risk of cardiovascular disease stems from that property and that property alone. The group of agents called cyclo-oxygenase type 2 (COX-2) inhibitors, being selective for anti-inflammatory activity, would not adversely affect the gastrointestinal tract. Neither picture, it has emerged, is that clear-cut. Later findings were to prove troublesome for COX-2 inhibitors, while new evidence has done no harm at all to the statins. Lowering C-reactive protein levels, indicating anti-inflammatory activity, provides extra clinical benefit from statins, argues paper #9 in the latest list. We must dig below the Top Ten for confirmation, from trials of the chemopreventive potential of COX-2 inhibitors, that patients on these drugs have increased risk of cardiovascular disease.

Dr. Paul M. Ridker and colleagues at Brigham and Women’s Hospital and Harvard Medical School, Boston, have long had an interest in the inflammatory marker C-reactive protein (CRP), and their research from the late 1990s had led to the hypothesis that statins, besides lowering circulating lipid levels, might have clinically important anti-inflammatory properties. Paper #9 from this group is confirmation of that idea. Ridker et al. used cutoffs of 70 mg/dL and 2 mg/L for "bad" (low-density lipoprotein) cholesterol and CRP, respectively, to generate four groups of patients participating in a randomized trial (reported elsewhere; see #3). Rates of recurrent myocardial infarction or death from a coronary cause were highest, at 4.6 per 100 patient-years, in the group whose LDL cholesterol remained at 70 mg/dL or above with CRP levels staying at 2 mg/L or higher. A combination of LDL-cholesterol less than 70 and CRP below 2 was best, at 2.4 per 100; there was nothing to choose between the other two possibilities. One might expect linked papers in the same issue of a journal to attract very similar citation rates but this appears not to have happened for the companion to Ridker and colleagues. S.E. Nissen et al. (New Engl. J. Med., 352[1]: 29-38, 2005) got more or less the same result, albeit in a smaller study with the different endpoint of disease progression determined by ultrasound, but with only 30 cites in the current Hot Papers file. (Both papers, however, ranked among the most-cited non-review reports published in 2005, as is noted on page 2 of this issue; none surpassed Ridker et al., at #1 for the year, while Nissen and colleagues wound up sixth.)

Again in the New England Journal of Medicine, this time in its issue for March 17, 2005, appear more chapters on the decline and fall of COX-2 inhibitors—three papers, in fact. In view of interest in the use of non-steroidal anti-inflammatory drugs to prevent colon cancer, it was natural for COX-2 inhibitors to be explored in this context. At #12, (S.D. Solomon, et al., New Engl. J. Med., 352[11]: 1071-80, 2005; with 34 citations recorded during September-October 2005) and at #15 (R.S. Bresalier, et al., New Engl. J. Med., 352[11]: 1092-102, 2005; 33 cites in the current bimonthly count) come papers recording increased cardiovascular events associated with both celecoxib (#12) and rofecoxib (#15) used in colorectal adenoma prevention trials. (These papers, too, appear high on the year-end list of 2005’s most cited: Solomon et al. at #3, Bresalier et al. at #4.)

That problems with COX-2 inhibitors are likely to be a class effect is evident from the fact that the above two studies were on different drugs. That view is supported by a third paper, sandwiched by the journal between the other two but not (yet) attracting quite the same attention. Valdecoxib and its intravenous prodrug parecoxib have been used in postoperative pain. In a placebo-controlled trial in patients after cardiac surgery, a worrying increase in cardiovascular events was found in patients given the active drug (N.A. Nussmeier, et al., New Engl. J. Med. 352(11): 1081-91, 2005; bimonthly count of 18 cites, with its overall year-end tally of 60 placing it at #16 among 2005’s most cited).

Mr. David W. Sharp, M.A. (Cambridge), is a
contributing editor to The Lancet, London, U.K.


	View the top 10 scientists and/or top 3 Hot Papers in Clinical Medicine.

Science Watch^®, March/April 2006, Vol. 17, No. 2
Citing URL: http://www.sciencewatch.com/march-april2006/sw_march-april2006_page5.htm