minocycline and Intracranial-Aneurysm

Tetracyclines may be useful in preventing pathological vascular remodeling, thus decreasing the risk of spontaneous hemorrhage from brain vascular malformations.. Arteriovenous malformation (AVM) and intracranial aneurysm patients undergoing noninvasive management were treated with minocycline or doxycycline (200 mg/day) up to 2 years in a prospective open-label safety pilot trial. The primary outcome was to compare dose-limiting intolerance, defined as treatment-related dose reduction or withdrawal between the agents.. Twenty-six patients with AVMs (n = 12) or aneurysms (n = 14) were recruited. Adverse event rates were similar to other reported trials of these agents; 4 of 13 (31%) minocycline and 3 of 13 (23%) doxycycline patients had dose-limiting intolerance (hazard ratio = 3.1, 95% CI = 0.52-18.11, log rank p = 0.70).. It is feasible to propose a long-term trial to assess the potential benefit of tetracycline therapy to decrease hemorrhagic risk in brain vascular malformations.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Doxycycline; Feasibility Studies; Follow-Up Studies; Humans; Intracranial Aneurysm; Intracranial Arteriovenous Malformations; Middle Aged; Minocycline; Pilot Projects; Prospective Studies; Treatment Outcome

An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT), can prevent the rupture of intracranial aneurysms.. Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage.. Minocycline and doxycycline significantly reduced rupture rates (vehicle versus doxycycline=80% versus 35%, P<0.05; vehicle versus minocycline=73% versus 24%, P<0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62% versus 55%, P=0.53).. Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.

Topics: Aneurysm, Ruptured; Animals; Blood Pressure; Disease Models, Animal; Doxycycline; Feasibility Studies; Gelatinases; Heterocyclic Compounds, 1-Ring; Intracranial Aneurysm; Male; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Minocycline; Neurologic Examination; Protease Inhibitors; Subarachnoid Hemorrhage; Sulfones; Survival Analysis; Tetracyclines