Upcoming Papers Stress Science Behind Sildenafil (Viagra)

Upcoming Papers Stress Science Behind Sildenafil
(Viagra)

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Sep- Oct 99	Rank Last Period Jul- Aug 99
1	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	55	4
2	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	53	3
3	S. Hulley, et al., "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women," JAMA-J. Amer. Med. Assoc., 280(7):605-13, 19 August 1998. [U. Calif. San Francisco; Johns Hopkins U., Baltimore, MD; Wake Forest U. Sch. Med., Winston-Salem, NC; Wyeth-Ayerst Res., Radnor, PA] *110ME	51	1
4	L. Hansson, et al., "Effects of intensive blood-pressure- lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	39	7
5	P.D. Delmas, et al., "Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women," New Engl. J. Med., 337(23):1641-7, 4 December 1997. [INSERM U 403, Lyons, France; Ctr. Clin. & Basic Res., Ballerup, Denmark; Lilly Res. Lab., Indianapolis, IN] *YJ871	34	6
6	J.A. Staessen, et al., "Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension," The Lancet, 350(9080):757-64, 13 September 1997. [14 institutions worldwide] *XW282	33	10
7	B. Fisher, et al., "Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study," J. Natl. Cancer Inst., 90(18):1371-88, 16 September 1998. [10 U.S. and Canadian institutions] *120NT	31	2
8	F.O. Nestle, et al., "Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells," Nature Medicine, 4(3):328-32, March 1998. [U. Zurich Med. Sch., Switzerland; U. Heidelberg, Germany; U. Munstervon, Munster, Germany] *ZN163	27	5
9	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	27	8
10	B. Dawson-Hughes, et al., "Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older," New Engl. J. Med., 337(10):670-6, 4 September 1997. [Tufts U., Boston, MA] *XU349	20	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

t is easy to forget, with all the publicity (and, inevitably, ribaldry) that accompanied the launch of sildenafil (Viagra), that there is a perfectly respectable pharmacological rationale behind this drug, and sound clinical evidence too. Currently ranking #14, with 18 citations this period, a clinical study from the Sildenafil Study Group (I. Goldstein, et al., "Oral sildenafil in the treatment of erectile dysfunction," New Engl. J. Med., 338(20):1397-1404, 1998) has yet to reach the top listing. It will.

The agent (messenger) responsible for the relaxation of smooth muscle upon which a man's erection depends is cyclic guanosine monophosphate (cGMP). Sexual stimulation causes a release of nitric oxide, and that prompts formation of cGMP via the enzyme adenyl cyclase. Another enzyme, phosphodiesterase, which occurs in several different forms, breaks down cGMP.

Any inhibitor of phosphodiesterase that targets preserving cGMP as a means of treating impotence needs to be enzyme type specific. Otherwise the side effects would be a major concern. Sildenafil is 1,000 times as potent an inhibitor for the type 5 enzyme that is relevant to erectile dysfunction as it is for type 3 (cardiac). There are heart drugs with specificity for type 3 phosphodiesterase. Sildenafil needs handling with special care where there is a history of cardiovascular disease. Another safety aspect being looked at is in respect of the eye. For example, C.M. Gonzalez and colleagues (in J. Impot. Res., suppl: s9-s14, 1999) record down-regulation by sildenafil of phosphodiesterase type 6 in rats. Transient visual disturbances, in the form of altered perception of color or brightness, have been reported clinically (e.g., in #14, where they seem to be dose-related.)

At least 20 double-blind trials have now been completed on sildenafil but hardly any clinical evidence was published by May 14, 1998, when paper #14 appeared. The drug had been licensed in the USA seven weeks earlier. More recent evidence includes studies in patients with diabetes or spinal-cord injury in whom erectile dysfunction can occur (see papers by M.S. Rendell, et al., in J. Amer. Med. Assoc., 281:421-6, 1999; and F. Giuliano, et al., in Ann. Neurol., 46:15-21, 1999) or with prostate cancer managed surgically or by radiotherapy. The Sildenafil Study Group looked at patients with a psychogenic, organic, or mixed cause for their problem; men with poorly controlled diabetes and spinal-cord injury, but not those with a history of radical prostatectomy, were excluded.

Question #3 in the International Index of Erectile Function asks about frequency of penetration (4 out of a maximum score of 5 would be normal). Baseline scores in these men were around 2. Scores rose in all three dose groups (but not in the placebo control group) and it doubled to around 4 for the 101 men on the 100 mg dose. In paper #14, the study group concludes that sildenafil seems to meet the American Urological Association's criteria for a reliable and safe agent that is also simple to use, for a medical disorder that is often undisclosed and undiscussed.

Mr. David W. Sharp, MA (Cambridge) is Deputy Editor of The Lancet, London, U.K.

Science Watch^Ž, January/February 2000, Vol. 11, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2000/sw_jan-feb2000_page5.htm