A super pill for the treatment of aneurysms

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Speaking at the VEITHsymposium, Dr Juan Parodi, Miami, discussed the treatment of abdominal aortic aneurysms (AAA) and hypothesised that in the future the alleviation of this condition maybe found through medicinal rather than through endovascular means. He began by stating that what was once thought as a simple degenerative process, aneurysm tissue is a highly active metabolically with ongoing synthesis and degradation of matrix proteins.

The pathophysiology of human AAA formation involves multiple factors including: biomechanical wall stress (treated with endografts); inflammation; proteolytic degradation; and genetics. Biopsies of AAAs have found that matrix metalloproteinases (MMPs) 8 and 9 expression were mediated by native mesenchymal cells and was independent of inflammatory infiltrate. Therefore, a localised increase in MMP-8 or MMP-9, mediated by native mesenchymal cells, presents a potential pathway for collagen breakdown and AAA rupture.

Histologically, AAAs are characterised by the destruction of elastin and collagen in the media and adventitia, smooth muscle cell loss with thining of the medial wall, infiltration of the lymphocytes and macrophages, and neovascularisation. All of which require a biological treatment.

He commented that there have been several attempts to use biological solutions, for example the use of growth factors to promote tissue encapsulation of stents or endografts. In addition, attempts have also been made to promote myointimal hyperplasia with the use of bare metal or absorbable stents. Finally, there has also been some use of biological manipulation with the use of MMP inhibitors, enhancement of TIPS, anti-inflammatory drugs and anti-oxidants.

Regarding myointimal hyperplasia, he analysed data on 36 patients who had survived for more than five years after endoluminal treatment of an AAA using the initial Parodi model. He found that there were no increases in neck diameter. Of the four specimens studied it was found that myointimal hyperplasia was very significant (0.7).

Based on this study, he began an experimental pilot study to examine whether myointimal hyperplasia prevents dilatation of the neck of AAAs. A preliminary study involved inducing AAAs in mice (with the application of Elastase or calcium chloride). The study found that aneurysm formation was prevented with the introduction of myointimal hyperplasia.

Next, Parodi discussed the use of MMP inhibitors such as Doxycyclin, Rapamycin and Simvastatin, as well as ACE inhibitors. He reported that an initial study in humans showed a decrease MMP concentration in blood and activity in the wall of aneurysms. No significant variation in aneurismal growth when administered for three months in the initial study, and reduction in the second.

In a prospective, doubled-blind, randomised, placebo-controlled study of 32 patients with AAAs, patient were randomly assigned to receive either Doxycyclin (150mg daily) or placebo during a three-month period and underwent ultrasound surveillance during an 18-month period. The aneurysm expansion rate in the doxycycline group was significantly lower than that in the placebo group during the 6- to 12-month (p=0.1) and the 12- to 19-months periods (p=01.).

“The evidence so far shows that Doxycyclin and statins have been effective in animals and that Doxycyclin produced a reduction in blood concentration in MMP-9 and MMP-2. In addition, Doxycyclin and statins reduced MMP activity on the aneurysmal wall,” he added.

He concluded that “With an increased knowledge of the biochemical mechanisms for aneurysm expansion, it may be possible to prevent or delay the growth of small aneurysms in the future.”

Date: Feb/2007

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