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Viagra May Help Crohn's Disease
      03/04/06 12:50 PM
HeatherAdministrator

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Crohn's Disease Etiology Questioned

By Jeff Minerd, MedPage Today Staff Writer
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
February 23, 2006
Also covered by: BBC, Forbes

LONDON, Feb. 23 - The exaggerated immune response that is considered part and parcel of Crohn's disease may have been exaggerated, reported investigators here.


In fact, Crohn's therapies aimed at reducing chronic inflammation may be doing more harm than good, reported Anthony W. Segal, F.R.S., and colleagues of University College London here in the February 25 issue of The Lancet.


Not only that, they suggested that one aspect of this weak response-sluggish blood flow in reaction to bacterial invaders-may be improved by Viagra (sildenafil).


Crohn's disease and colitis, known collectively as inflammatory bowel diseases, affect approximately 1.4 million Americans, including some 140,000 children under the age of 18, according to the Crohn's and Colitis Foundation of America.


Compared with 13 healthy controls, 13 patients with Crohn's disease produced abnormally low levels of neutrophils and the inflammatory cytokine interleukin 8 in response to experimental wounds and abrasions (with sandpaper) the researchers made at various sites on the body.


Neutrophil production was 79% lower than normal in the rectum (P=.0003) and 50% of normal in the skin (P<.0001). IL-8 levels were 63% lower in the rectum (P=.003) and 45% lower in the skin (P<.0001), the investigators reported.


To assess response to the presence of bacteria, the researchers injected heat-killed Escherichia coli under the skin of study participants. Healthy controls showed a vigorous inflammatory response, characterized by redness, swelling, and increased blood flow.


While superficially similar, the responses of Crohn's patients were characterized by sluggish increases in blood flow. Blood flow was reduced by 77% compared with controls in patients with colonic disease (P=.0003) and by 50% compared with controls in patients with ileal disease (P=.01).


Oral administration of 50 mg of Viagra to Crohn's patients after the bacterial injection markedly increased blood flow, bringing it up to normal or near-normal in half of the individuals within 30 minutes, the investigators said.


The researchers also tested three patients with ulcerative colitis, but the responses of these patients were more similar to the control participants than to the patients with Crohn's disease, suggesting that ulcerative colitis has a different etiology than Crohn's, the authors said.


The authors believe that in Crohn's disease, reduced or delayed recruitment of neutrophils to sites at which bacteria penetrate the intestinal wall might lead to the persistence of bacteria and other organic debris in the tissue. The body may respond to this buildup of bacteria by secreting inflammatory molecules, which accumulate and lead to the chronic inflammation typical of Crohn's.


"Causation of Crohn's disease by failure of the acute inflammatory response would fit very well with the so-called hygiene hypothesis, in which the increased incidence of the disease has been attributed to improved standards of sanitation," the authors wrote, noting that incidence of the disease rose greatly in the latter part of the 20th century.


"These findings provide hope for the development of more effective therapies for Crohn's disease," the authors said. Current treatments are immunosuppressive, but although they reduce symptoms by dampening the proposed secondary inflammation, they might actually accentuate the underlying immunodeficiency.


A more successful treatment approach might be to introduce IL-8 or other proinflammatory stimuli directly into acute lesions, either by direct enteral administration or through synthesis by genetically modified gut organisms, they proposed.


"Agents that increase blood flow, such as long-acting phosphodiesterase-5 inhibitors or other vasodilatatory or proinflammatory drugs, might be useful in healing or preventing lesions in Crohn's disease," they concluded.



Primary source: The Lancet
Source reference:
Marks DJB et al. Defective acute inflammation in Crohn's disease: a clinical investigation. The Lancet. 2006; 367:668-678.

http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/dh/2737

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