Pharmacologic suppression of experimental abdominal aortic aneurysms: A comparison of doxycycline and four chemically modified tetracyclines John A.

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Presentation transcript:

Pharmacologic suppression of experimental abdominal aortic aneurysms: A comparison of doxycycline and four chemically modified tetracyclines John A. Curci, MD, Drazen Petrinec, MD, Shixiong Liao, MD, Lorne M. Golub, DMD, MSc, Robert W. Thompson, MD Journal of Vascular Surgery Volume 28, Issue 6, Pages 1082-1093 (December 1998) DOI: 10.1016/S0741-5214(98)70035-7 Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 1 Chemical structures of tetracycline derivatives. A, Chemical groups responsible for different biologic activities of tetracycline derivatives are outlined on structure of tetracycline nucleus. The 4-dimethylamino group is required for antibiotic activity (single arrow), and the 11-oxy and 12-hydroxy groups are responsible for direct metalloproteinase inhibition (split arrow). B, Doxycycline (6-deoxy, 5-hydroxy tetracycline). C, CMT-3 (6-dimethyl, 6-deoxy, 4-dedimethylamino tetracycline. D, CMT-4 (7-chloro, 4-dedimethylamino tetracycline). E, CMT-7 (12-deoxy, 4-dedimethylamino tetracycline). F, CMT-8 (6-deoxy, 5-hydroxy, 4-dedimethylamino tetracycline). Modifications in each of the nonantibiotic CMTs predominantly influence their biologic availability and pharmacokinetic properties, without diminishing antimetalloproteinase potency. Journal of Vascular Surgery 1998 28, 1082-1093DOI: (10.1016/S0741-5214(98)70035-7) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 2 Dose-dependent inhibition of aortic dilatation with doxycycline. Rats were treated with subcutaneous doxycycline at doses indicated for 7 days after elastase-induced aortic injury. Final aortic diameter was determined for 6 animals in each treatment group. For each dose of doxycycline, mean reduction in aortic diameter is expressed as percentage (mean ± standard error of the mean) of that observed in controls treated with saline solution alone. Maximal inhibitory effects were observed at doses greater than 30 mg/kg/day, and half-maximal inhibition was calculated at a dose of approximately 5.9 mg/kg/day. *P < .05 versus saline-solution controls, analysis of variance and Student-Newman-Keuls multiple comparisons test.†P < .05 versus previous dose, Student t test. Journal of Vascular Surgery 1998 28, 1082-1093DOI: (10.1016/S0741-5214(98)70035-7) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 3 Relative inhibition of aortic dilatation with doxycycline and chemically modified tetracyclines (CMTs). Rats were treated with subcutaneous injection with 15 mg/kg/day of doxycycline or with 1 of 4 CMTs for 7 days after elastase-induced aortic injury. For each treatment group, mean reduction in final aortic diameter is expressed as percentage (mean ± standard error of the mean) of that observed in controls treated with saline solution alone. There were no significant differences between the inhibitory effects of doxycycline versus any of the 4 CMTs (P > .05, Student t test). Solid bar, Doxycycline; hatched bars, individual CMTs; open bar, pooled data for all 4 CMTs. Journal of Vascular Surgery 1998 28, 1082-1093DOI: (10.1016/S0741-5214(98)70035-7) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 4 Structural changes in elastase-perfused rat aorta induced by treatment with tetracycline derivatives. Rat tissue specimens were obtained 7 days after aortic perfusion and stained with Verhoeff–van Gieson stain. This stain displays elastic fibers in black and collagen fibers in red. A, Perfusion with saline solution, no treatment. B, Perfusion with porcine pancreatic elastase (PPE), treatment with saline solution alone. C, Perfusion with PPE, treatment with 7.5 mg/kg/day doxycycline. D, Perfusion with PPE, treatment with 15 mg/kg/day doxycycline. E, Perfusion with PPE, treatment with 30 mg/kg/day doxycycline. F, Perfusion with PPE, treatment with 15 mg/kg/day CMT-7. Original magnification, 60×. Journal of Vascular Surgery 1998 28, 1082-1093DOI: (10.1016/S0741-5214(98)70035-7) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 5 Effect of tetracyclines on matrix metalloproteinase activities extractable from elastase-injured rat aorta. Rats were treated with tetracycline derivatives for 7 days after elastase-induced aortic injury. Aortic tissue extracts were normalized to total protein concentration and examined by gelatin substrate zymography. A, Gelatinase activities in extracts from rats treated with varying doses (0 to 60 mg/kg/day) of doxycycline. B, Gelatinase activities in extracts from rats treated with doxycycline or chemically modified tetracyclines at 15 mg/kg/day. C, Calculated relative density corresponding to 92-kD and 72-kD gelatinase activities detected in A (percent of normal aorta). D, Calculated relative density corresponding to 92-kD and 72-kD gelatinase activities detected in B (percent of normal aorta). Journal of Vascular Surgery 1998 28, 1082-1093DOI: (10.1016/S0741-5214(98)70035-7) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions