Textbook of Interventional Cardiovascular Pharmacology - part 5 pps

1180 Chap19 3/14/07 11:29 AM Page 240 Introduction Investigations have shown that iron may contribute to endothelial cell function and increase the risk of cardiovascular disease. It is believed that strong metal chelators such as deferoxamine (DFO) can counteract iron cation formation. The primary targets of iron chelators used for treating iron overload are prevention of iron ingress into tissues and its intracellular scavenging. Iron Body iron stores An average adult human absorbs and excretes (in iron balance) ~1 mg of iron each day. Even slight disturbances in this balance may lead to general or local iron overload or iron deficiency. Iron is essential for all cells for heme synthesis and obtained from extracellular transferrin. Mitochondrial and extramitochondrial cytochromes, oxygen-storage proteins, and hemoglobin and myoglobin are needed in heme iron. The liver is adapted to store and release iron when needed. Normally, all cells regulate the suitable level of catalytically active iron pool during iron uptake, synthesis of iron-containing proteins, and iron release. Excess iron can interact with oxygen to form very toxic superoxide and hydroxyl radicals. Several points are important to cardiovascular pharmacology in the case of iron overload: damage of endothelium as a base for development of atherosclerosis and tissue ischemia, existence in the iron pool of a weakly bound low-molecular- weight iron complex, and the possibility of the iron chelating drugs (DFO) interacting with this chelatable iron. Iron and endothelial function Nonprotein-bound iron may directly inactivate endothelium- derived nitric oxide (1), depress endothelial dysfunction, and be a potential mechanism for iron-related cardiovascular disease (2). Because the endothelium participates in the release of several paracrine factors, including nitric oxide, it is critical in regulating vasomotor tone, platelet activity, leuko- cyte adhesion, vascular smooth muscle proliferation, and endothelial activation (3). Large amounts of immunoreactive ferritin are focally detected in atherosclerotic lesions, specifi- cally in endothelium. Endothelial dysfunction could potentially explain the association between iron and cardiovascular events, because endothelial dysfunction is commonly present in patients with atherosclerosis (2,4). Iron and cardiovascular disease Body iron level and iron depletion play an important role in the gender differences seen in death from cardiac disease. There is a better correlation with heart disease mortality in iron levels compared with levels of cholesterol (5). It was found that risk of coronary heart disease (6) and carotid atherosclerosis (7) is associated with increased iron stores. However, impaired endothelium-derived nitric oxide activity may be without overt atherosclerosis in patients with risk factors and may be associated with the presence of atherosclerosis (4). Thus, endothelial dysfunction related to iron activity not only may be an early marker for cardiovascular risk but also may contribute to the pathogenesis of atherosclerosis (2) by the stimulation of low-density lipoproteins (LDL) and membrane lipid peroxidation (1) and may be a key to the understanding of early mechanism in the development of atheroma (7,8). Nakayama et al. (9) showed the role of heme oxygenase induction in the modulation of macrophage activation in atherosclerosis. However, Howes et al. (10) concludes that at the moment, the available evidence on iron hypothesis remains circumstantial. Moreover, Kiechl et al. (7) showed that the adverse effect of iron is hypercholesterolemia. In patients 20 Iron chelation: deferoxamine and beyond Valeri S. Chekanov 1180 Chap20 3/14/07 11:30 AM Page 241 referred for coronary angiography, higher ferritin concentration and transferrin saturation levels were not associated with an increased extent of coronary atherosclerosis (11). Results of Hetet et al. (12) do not support the hypothesis that reduced body iron stores lower coronary heart disease risk. Minqin et al. (13) and You et al. (14) confirm the role of iron in damage and progression of this disease. Stadler et al. (15) showed that cholesterol levels correlated positively with iron accumulation and that iron may contribute to disease progression. It is believed that myocardial iron deposition and the resultant cardiomyopathy only occurs in the presence of severe liver iron overload (16). A lower concentration of vitamin C and higher levels of labile iron pool may create an environment that promotes the development of atherosclerosis (17). A relation- ship between serum ferritin levels and carotid atherosclerosis in clinic was confirmed by Wolff et al. (18). Pharmacology of deferoxamine Structure and chemistry DFO is an iron-chelating agent with a molecular weight of 657. Acetic acid, succinic acid, and 1-amino-5- hydroxylaminopentane are the three distinct moieties that compose DFO. They form an open-chain molecule with three amino groups and three hydroxamic acid groups. In each hydroxamic acid group, DFO has two coordination sites for iron (III) (six together). This hexadentate structure allows it to react with ferric ion, its chain structure entwining completely around the central ferric ion (19). As a result, the very stable (and protected from enzymatic degradation) DFO–iron complex (ferrioxamine) is formed. It is very important that other metal ions have no affinity to DFO and the treatment with DFO did not result in the depletion of other important metal ions from the body (19). For clinical treatment, DFO mesylate is used in sterile, lyophilized form (500 mg or 2 g in sterile, lyophilized form). DFO mesylate is a white powder, freely soluble in water. DFO mesylate is N- [5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamido] pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl] pro-pionohydroxamic acid mono- methanesulfonate (salt), and its structured formula of deferoxamine mesylate is shown in Figure 1. Clinical pharmacology The mechanism of action of DFO is the formation of a stable complex with iron. It prevents the iron from entering into further chemical reactions. It is important that DFO chelates iron from hemosiderin and ferritin, but not from transferrin. It does not bind with the iron from hemoglobin and cytochromes. It is theorized that DFO is metabolized by plasma enzymes. The chelate is soluble in water and passed easily through the kidney (reddish color of urine). Plasma pharmacokinetics DFO may easily be absorbed from the gut and parenteral use is very efficient. If administered intravenously, DFO is eliminated from the systemic circulation very rapidly and in a biphasic manner (19). Both DFO and its major metabolites are cleared by the kidney and liver. However, ferrioxamine (DFO–iron complex) is cleared exclusively by the kidneys (19) and in the case of renal disease may accumulate in plasma and must be eliminated by dialysis. Access to chelatable iron pools The majority of body iron is not chelatable (iron from cytochromes and hemoglobin). There are two major pools of chelatable iron by DFO (19). The first is that delivered from the breakdown of red cells by macrophages. DFO competes with transferrin for iron released from macrophages. DFO will also compete with other plasma proteins for this iron, when transferrin becomes saturated in iron overload. The quantity of chelatable iron from this turnover is 20 mg/day in healthy individuals and iron chelated from this pool is excreted in the urine (19). The second major pool of iron available to DFO is derived from the breakdown of ferritin and hemosiderin. The ferritin is catabolized every 72 hours in hepatocytes, predominantly within lysosomes (1). DFO can chelate iron that remains within lysosomes shortly after ferritin catabolism or once this iron reaches a dynamic, transiently chelatable, cytosolic low-molecular- weight iron pool (20). Cellular iron status, the rate of uptake of exogenous iron, and the rate of ferritin catabolism are influ- ent on the level of a labile iron pool (21). Excess ferritin and 242 Iron chelation: deferoxamine and beyond H 2 N(CH 2 ) 5 NC(CH 2 ) 2 CNH(CH 2 ) 5 NC(CH 2 ) 2 CNH(CH 2 ) 5 NCCH 3 . CH 3 SO 3 H OH OH OH O O O O O Figure 1 Structural formula of deferoxamine. 1180 Chap20 3/14/07 11:30 AM Page 242 hemosiderin are turned over less often in myocytes than in the hepatocyte. This explains (16) why intensive chelation with DFO results in more rapid decrease in liver iron than in heart iron. Because of its hydrophilicity and relatively high molecular weight, DFO tends to move slowly across biomembranes. The rate of formation of intracellular iron chelate complexes is also slow (19). As a result, some nonheme-iron-containing enzymes (lipoxygenase) are not inhibited by DFO. Thus, the properties that limit DFO moving across biomembranes also limit access to metaboli- cally important metal ion pools, thereby decreasing its potential toxicity (19). Mechanism of action in myocardium Anderson et al. (16) and Davis and Porter (19) believe that the more rapid chelation of the potentially toxic labile intracellular iron may explain the rapid reversal of cardiac dysarrhythmias and improvement in ventricular function with continuous DFO infusion, prior to achieving large decre- ments in myocardial iron. In experimental models, iron overload has been found to increase myocardial damage caused by anoxia and reperfusion, and the use of the iron chelator DFO resulted in a decrease in myocardial damage and protection of myocardial performance (22). Moreover, DFO significantly improved systolic function in both newborn and adults hearts exposed to 40 minutes of ischemia (23). The findings from the study of Nicholson et al. (24) indicated that there is protection against ischemia–reperfusion injury when DFO is added to the cardioplegic solution. Indication, contraindication, and usage General indication DFO is generally indicated for treatment of acute iron intoxication and chronic iron overload due to transfusion depended anemias (including thalassemia). DFO is not recommended in primary hemochromatosis (PDR). Contraindications DFO is contraindicated in patients with severe renal disease or anuria as both DFO and the iron chelate are excreted primarily by the kidney. During pregnancy, DFO should be used only if clearly indicated (PDR). Warnings DFO causes a number of allergic reactions, including pruritus, wheals, rash, and anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg cramps, and tachycardia. Ocular disturbances may occur over prolonged periods of DFO use, or at high doses, or in patients with low ferritin levels. These include blurring of vision, cataracts, visual loss, visual defects, impaired peripheral, color and night vision, optic neuritis, corneal opacities, and retinal pigmentary abnormalities. Rapid development of severe toxic retinopathy associated with continuous intravenous DFO infusion was reported by Lai et al. (25). Auditory disturbances may occur after long-term use of DFO, including tinnitus, hearing loss, and especially high-frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances are reversible upon immediate cessation of treatment (26). A “pulmonary syndrome” (tachypnea, hypoxemia, fever, eosinophilia) was reported after high-dose (10–25 mg/kg/hr) DFO (27). Precautions and drug interactions Impairment of cardiac function may follow concomitant treatment with DFO and high doses of vitamin C (Ͼ500mg/day). However, when vitamin C was discontinued, cardiac function was reversible. Patients with iron overload usually become vitamin C deficient (iron oxidizes the vitamin). Vitamin C increases availability of iron for chelation. Therefore, vitamin C should not be given to patients with cardiac failure and started only after an initial month of regular treatment with DFO. Clinical monitoring of cardiac function is advisable during such combined therapy (PDR). Hypotension and shock have occurred in a few patients when DFO was administrated by rapid intravenous injection. Thus, DFO should be given intra- muscularly or by slow subcutaneous or intravenous infusion (PDR). Concurrent treatment with prochlorperazine (a phenothiazine derivative) may lead to temporary impairment of consciousness (PDR). In some patients, the following adverse reactions have been observed at the injection site: irri- tation, pain, burning, swelling, indurations, infiltration, pruritus, erythema, crust, vesicles, and local edema (PDR). Some patients with hypersensitivity reaction may experience the following: hypotension, shock, abdominal discomfort, diarrhea, vomiting, blood dyscrasia, leg cramps, dizziness, neuropathy, paresthesias, dysuria, and impaired renal function (PDR). Overdosage Signs and symptoms: hypotension, tachycardia, transient loss of vision, aphasia, agitation, nausea, pallor, central nervous Indication, contraindication, and usage 243 1180 Chap20 3/14/07 11:30 AM Page 243 system depression (including coma), bradycardia, and acute renal failure (PDR). There is no specific antidote. DFO should be discontinued immediately. Dosage and administration DFO is preferably dissolved by adding 5 mL of sterile water for injection to each 500 mg vial or 20 mL of sterile water for injection to each 2 g vial. DFO reconstituted for injection is for single-use only. Acute iron intoxication Intramuscular administration is preferred and should be used for all patients not in shock. The intravenous route should be used only for patients in a state of cardiovascular collapse and then only by slow infusion. The rate of infusion should not exceed 15 mg/kg/hr for the first 1000 mg administrated. Subsequent IV dosing, if needed, must be at a slower rate, not to exceed 125 mg/hr. Chronic iron overload A daily dose of 500 to 1000 mg should be administrated intra- muscularly; in addition, 2000 mg should be administrated intravenously with each unit of blood, but separately from the blood. The rate of IV transfusion must not exceed 15 mg/kg/hr. The total daily dose 1000 mg in the absence of a transfusion, but may be upto 6000 mg if three or more units of blood are transfused. For subcutaneous administration, a daily dose of 1000 to 2000 mg should be used (20–40 mg/kg/day) over 8 to 24 hours (PDR). Special application in cardiology Experimental data Atherosclerosis In animal models of atherosclerosis, vascular iron deposit is closely related to the progression of atherosclerosis and LDL oxidation, and restriction in dietary iron intake leads to significant inhibition of lesion formation (8). DFO forms a stable complex with ferric iron and decreases its availability for the production of reactive-oxygen species (28). Moreover, in high concentration (Ͼ0.5 mmol/L), DFO may also scavenge reactive-oxygen species (28). Matthews et al. (29) confirmed that iron chelators possess antioxidant activity in vitro and may reduce atherogenesis in vivo. Recently, Minqin et al. (13) showed that the iron chelator inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit. Muscle tissue ischemia During ischemia, iron is released from erythrocytes. This increased iron level is cytotoxic to the vascular endothelium and acts as a catalyst for reactive-oxygen metabolism (30). DFO has been shown recently to activate the angiogenesis response (31). Some investigations also showed that DFO is effective in treatment of ischemic syndromes (32,33). DFO may attenuate the deleterious effects of iron on muscular tissue and has protected human endothelial cells in vitro from reoxygenation injury (34). DFO has recently been shown to be active in the treatment of acute ischemic syndrome (35,36). For local treatment of ischemia, a combination of DFO with fibrin sealant shows promising results: fibrin enhances angiogenesis and serves as a vehicle for delivering angiogenic growth factors (36). Local DFO application may be used to successfully promote neovascularization of ischemic tissue and is sufficient to revascularize an ischemic lower limb without damaging ischemic tissue. Fibrin sealant can activate migration of endothelial cells, macrophages, and myofibroblasts toward treated ischemic tissue, serving as a temporary matrix for gradual development of granulation tissue that is characterized by a high degree of vascularity, resulting in a new vessel formation within a loose collagenous interstitium (33,36). Studies (37) have shown that adding vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to the fibrin network increases angiogenesis in ischemic tissue and promotes sprout formation through enhancing the effect of the fibroblasts, vascular smooth muscle cells (VSMCs), and pericytes. Intracellular iron chelation indirectly stimulates endothelial cell growth by increasing VEGF release by VSMCs (38). Recently, Ulubayram et al. (39) confirmed that gelatin-based, controlled-release systems could be improved and could be good candidates for the production of long-term DFO- carrying systems. When DFO in fibrin sealant was applied in the case of acute limb ischemia (femoral artery excision), both angiogenesis and arteriogenesis were affected (Fig. 2) (36). Initial evidence based on arteriography and histological (immunostaining) studies indicated that angiogenesis improved to compensate for diminished blood flow in the ischemic limb (i.e., more capillaries occupied the same percentage of area as before surgery or, in some cases, even more of the area) as did arteriogenesis (i.e., more newly developed arterioles or remodeled pre-existing ones grew to become large collateral arteries). 244 Iron chelation: deferoxamine and beyond 1180 Chap20 3/14/07 11:30 AM Page 244 Protection from reperfusion injury DFO is known to reduce the iron-dependent generation of toxic oxygen-derived radicals during reperfusion of ischemic tissue (40). It was shown experimentally that DFO reduces the early inflammatory reaction and improves myocardial microcirculation (41). Moreover, Dross et al. (42) showed that DFO’s scavenging effect on superoxide anion could play a role in the cellular defense against oxygen radicals during cardiac operation. Clinical evidence of cardioprotective effect Reversal of established heart disease In most cases, the reversal of symptomatic myocardiopathy has been achieved without drug toxicity (19,43). Davis and Porter (19) and Tsironi et al. (44) confirmed clinically the labo- ratory data of Link et al. (45) that DFO therapy reverses cardiac arrhythmias in some patients previously unresponsive to medical treatment. This may be attributed to removal of a toxic labile iron pool. They also mentioned improvement of left ventricular ejection fraction in seven of nine patients. It is important to note that oral chelators are less effective than DFO and are unable to prevent cardiac mortality in patients with established heart disease (46). Coronary artery atherosclerosis Duffy et al. (2) showed that DFO improved endothelium- dependent vasodilatation in patients with coronary artery disease. In his review of 68 references regarding iron- mediated cardiovascular injury, Horwitz and Rosenthal (47) concluded that iron chelation may prevent restenosis and atherogenesis in coronary arteries. Paraskevaidis et al. (48) demonstrated that in patients undergoing elective coronary artery bypass grafting for the first time, the infusion of the free-radical scavenger DFO, for eight hours, starting immediately after the induction of anesthesia, improves the postischemic recovery of the left ventricle, mainly in those patients with the poorest pre-operative cardiac function. Of particular interest, this benefit remains for 12 months of follow-up. Future chelation therapy For 30 years, DFO has been the only approved iron chelator. Recently, several oral iron chelators and variations of DFO to prolong the half-life have been developed. The best conclu- sion for the future of chelation therapy in cardiology was done by Hershko et al. in 2005 (49): “Prevention of cardiac mortality is the most important beneficial effect of iron chelation therapy. Unfortunately, compliance with the rigorous requirements of daily subcutaneous DFO infusions is still a serious limiting factor in treatment success. The development of orally effective iron chelators such as deferiprone and ICL670 (deferasirox) is intended to improve compliance. Although total iron excretion with deferiprone is somewhat less than that with DFO, deferiprone may have a better cardioprotective effect than DFO due to deferiprone’s ability to penetrate cell membranes. For the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available to avoid serious organ damage. Finally, combined chelation treatment is emerging as a reasonable alternative to chelator monotherapy. Combining a weak chelator that has a better ability to penetrate cells with a stronger chelator that pene- trates cells poorly but has a more efficient urinary excretion may result in improved therapeutic effect through iron shut- tling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likeli- hood of success in patients previously failing DFO or deferiprone monotherapy.” Special application in cardiology 245 Figure 2 Angiogram one month after excision femoral artery and application deferoxamine in fibrin sealant. Many new collaterals formed to the distal part of femoral artery. 1180 Chap20 3/14/07 11:30 AM Page 245 References 1 Cooper CE. Nitric oxide and iron proteins. Biochim Biophys Acta 1999; 340:115–126. 2 Duffy SJ, Biegelsen ES, Holbrook M, et al. Iron chelation improves endothelial function in patients with coronary artery disease. Circulation 2001; 103:2799–2804. 3 Zhang WJ, Frei B. Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells. Free Radic Biol Med 2003; 34(6):674–682. 4 Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340:1111–1115. 5 Lauffer RB. Iron stores and the international variation in mortality from coronary artery disease. Med Hypoth 1991; 35:96–102. 6 de Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 1999; 159:1542–1548. 7 Kiechl S, Willeit J, Egger G, et al. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 1997; 96:3300–3307. 8 Lee TS, Shiao MS, Pan CC, et al. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation 1999; 99:1222–1229. 9 Nakayama M, Takahashi K, Komura T, et al. Increased expression of heme oxygenase-1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2001; 21(8):1373–1377. 10 Howes PS, Zacharski LR, Sullivan J, Chow B. Role of stored iron in atherosclerosis. J Vasc Nurs 2000; 18(4):109–114. 11 Auer J, Rammer M, Berent R, et al. Body iron stores and coronary atherosclerosis assessed by coronary angiography. Nutr Metab Cardiovasc Dis 2002; 12(5):285–290. 12 Hetet G, Elbaz A, Gariepy J, et al. Associated studies between haemochromatosis gene mutations and the risk of cardiovascular disease. Eur J Clin Invest 2001; 31(5):382–388. 13 Minqin R, Watt F, Huat BT, Halliwell B. Correlation of iron and zinc levels with lesion depth in newly formed atherosclerotic lesions. Free Radic Biol Med 2003; 34(6):746–752. 14 You SA, Archacki SR, Angheloiu G, et al. 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Association between high serum ferritin levels and carotid atherosclerosis in the study of health in Pomerania (SHIP). Stroke 2004; 35(2):453–457. 19 Davis BA, Porter JB. Results of long term iron chelation treatment with deferoxamine. In: Hershko C, ed. Advances in Experimental Medicine and Biology. Vol. 509. New York: Kluwer Academic/Plenum Publisher, 2002. 20 Konijn AM, Glickstein H, Vaisman B, et al. The cellular labile iron pool and intracellular ferritin in K562 cells. Blood 1999; 94:2128–2134. 21 Epsztejn S, Kakhlon O, Glickstein H, et al. Fluorescence analysis of the labile iron pool of mammalian cells. Anal Biochem 1997; 248:31–40. 22 Araujo A, Kosaryan M, MacDowell A, et al. A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload. Br J Haematol 1996; 93:835–837. 23 Nakamura H, del Nido PJ, Jimenez E, et al. Age-related differences in cardiac susceptibility to ischemia/reperfusion injury. Response to deferoxamine. J Thorac Cardiovasc Surg 1992; 104(1):165–172. 24 Nicholson SC, Squier M, Ferguson DJ, et al. Effect of desferrioxamine cardioplegia on ischemia-reperfusion injury in isolated rat heart. Ann Thorac Surg 1997; 63(4): 1003–1011. 25 Lai TY, Lee GK, Chan WM, Lam DS. Rapid development of severe toxic retinopathy associated with continuous intravenous deferoxamine infusion. Br J Ophthalmol 2006; 90(2): 243–244. 26 Chen SH, Liang DC, Lin HC, et al. Auditory and visual toxicity during deferoxamine therapy in transfusion- dependent patients. J Pediatr Hematol Oncol 2005; 27(12): 651–653. 27 Freedman MH, Grisaru D, Olivieri N, et al. Pulmonary syndrome in patients with thalassemia major receiving intravenous deferoxamine infusions. Am J Dis Child 1990; 144:565–569. 28 Halliwell B. Use of desferrioxamine as a probe for iron- dependent formation of hydroxyl radicals. Evidence for a direct reaction between desferal and the superoxide radical. Biochem Pharmacol 1985; 34(2):229–233. 29 Matthews AJ, Vercellotti GM, Menchaca HJ, et al. Iron and Atherosclerosis: inhibition by the iron chelator deferiprone. J Surg Res 1997; 73:35–40. 30 Muntane J, Mitjavila MT, Rodriquez MC, et al. Dietary lipid and iron status modulate lipid peroxidation in rats with induced adjuvant arthritis. J Nutr 1995; 125(7):1930–1937. 31 Chawla PS, Keelan MN, Kipshidze N. Angiogenesis for treatment of vascular diseases. Int Angiol 1999; 18 (3): 185–192. 32 Baffour R, Garb JL, Kaufman J, et al. Angiogenic therapy for the chronically ischemic lower limb in a rabbit model. J Surg Res 2000; 93(2):219–229. 33 Chekanov VS, Nikolaychik VV. Iron contributes to endothelial dysfunction in acute ischemic syndrome. Circulation 2002; 105(4):E35. 34 Hickey MJ, Knight KR, Lepore DA, et al. Influence of postischemic administration of oxyradical antagonists on ischemic injury to rabbit skeletal muscle. Microsurgery 1996; 17(9):517–523. 35 Beerepoot LV, Shima DT, Kuroki M, et al. Up-regulation of vascular endothelial growth factor production by iron chelator. Cancer Res 1996; 56(16):3747–3751. 36 Chekanov VS, Zargarian M, Baibekov IM, et al. Deferoxamine- fibrin accelerates angiogenesis in a rabbit model of peripheral ischemia. Vasc Med 2003; 8(3):157–162. 246 Iron chelation: deferoxamine and beyond 1180 Chap20 3/14/07 11:30 AM Page 246 37 Pandit AS, Feldman DS, Caulfield J, Thompson A. Stimulation of angiogenesis by FGF-1 delivered through a modified fibrin scaffold. Growth Factors 1998; 15(2):113Ϫ123. 38 Hodges YK, Reese SM, Pahl PM, Horwitz LD. Paradoxical effects of iron chelation on growth of vascular endothelial cells. J Cardiovasc Pharmacol. 2005; 45(6): 539–544. 39 Ulubayram K, Kiziltay A, Yilmaz E, Hasirei H. Desferrioxamine release from gelatin-based systems. Biotechnol Appl Biochem 2005; 42(Pt 3):237–245. 40 Spencer KT, Lindower PD, Buettner GR, Kerber RE. Transition metal chelators reduce directly measured myocardial free radical production during reperfusion. J Cardiovas Pharmacol 1998; 32(3):343–348. 41 Dulchavsky SA, Davidson SB, Cullen WJ, et al. Effects of deferoxamine on H 2 O 2 -induced oxidative stress in isolated rat heart. Basic Res Cardiol 1996; 91(6):418–424. 42 Dross G, Lazou A, Panagopoulos P, et al. Deferoxamine cardioplegia reduces superoxide radical production in human myocardium. Ann Thorac Surg 1995; 59(1):169–172. 43 Hershko C, Link G, Konijn AM. Cardioprotective effect of iron chelators. In: Hershko C, ed. Advances in Experimental Medicine and Biology. Vol. 509. New York: Kluwer Academic/ Plenum Publisher, 2002. 44 Tsironi M, Deffereos S, Andriopoulos P, et al. Reversal of heart failure in thalassemia major by combined chelation therapy: a case report. Eur J Haematol 2005; 74(1):84–85. 45 Link G, Saada A, Pinson A, et al. Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. J Lab Clin Med 1998; 131:466–474. 46 Hoffbrand AV, Al-Refaie F, Davis B, et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood 1998; 91:295–300. 47 Horwitz LD, Rosenthal SA. Iron-mediated cardiovascular injury. Vasc Med 1999; 4(2):93–99. 48 Paraskevaidis IA, Iliodromitis EK, Vlahakos D, et al. Deferoxamine infusion during coronary artery bypass grafting ameliorates lipid peroxidation and protects the myocardium against reperfusion injury: immediate and long-term significance. Eur Heart J 2005; 26(3):263–270. 49 Hershko C, Link G, Konijn AM, Cabantchik ZI. Objectives and mechanism of iron chelation therapy. Ann N Y Acad Sci 2005; 1054:124–135. References 247 1180 Chap20 3/14/07 11:30 AM Page 247 1180 Chap20 3/14/07 11:30 AM Page 248 Coronary stent implantation prevents vessel elastic recoil and reduces restenosis in some subsets of lesions compared to balloon angioplasty alone. However, because of inducing a foreign body reaction and causing deep vessel injury during stent deployment, sub(acute) thrombosis and increased neointimal hyperplasia have limited their efficacy. Systemic drug administration has been limited by side effects and insuf- ficient drug concentration at the target sites. Stent, uncoated or coated with polymer matrix, has been proposed as a plat- form for local drug delivery. Stent mediated local drug delivery could achieve a high local drug concentration and sustained drug release. Until now, different stents, polymer coatings, and drugs have been explored to reduce stent-related thrombosis and to suppress the cascade of neointimal formation. Thromboresistant stents Optimal stent implantation and new antiplatelet therapy have reduced the thrombotic complication after stent implantation, dramatically. However, thrombosis remains a challenge in some lesions and patient subgroups. As an initial and unavoid- able event during stent implantation, thrombosis and platelet activation are also involved in the development of neointimal hyperplasia. Stents coated with heparin and other antithrom- botic drugs have been demonstrated to decrease thrombotic complications, although their effect on neointimal hyperplasia remains uncertain. As heparin is attached to the stent surface, we divide thromboresistant stents as heparin-coated stents and drug-eluting thromboresistant stents. Heparin-coated stents Heparin is an antithrombin III factor. It can be attached to a metallic surface either chemically or physically. Endpoint covalent attachment of heparin to a polymer-coated surface is a stable and efficient method. By this bond, the immobilized heparin interacts with circulating antithrombin III. In vitro experimental work showed that heparin-coated stents could decrease the platelet aggregation and thrombus weight (Table 1). Furthermore, most in vivo studies demonstrated that heparin-coated stents could reduce stent thrombogenic- ity. For the effects on neointimal hyperplasia, controversial results have been published. Most studies showed that heparin-coated stents have a limited effect on neointimal hyperplasia. Even in one study, histomorphometric analysis after four weeks showed a significant increase in neointimal thickness with the highest heparin activity, although no significant difference was observed at 12 weeks follow-up (1). Heparin also has interactions with several growth factors and other glycoproteins (GPs). By this way, the heparin coating could hamper endothelial cell coverage of the coated stents. However, two recent studies in pigs have found that heparin- coated stents could decrease neointimal hyperplasia compared to bare control stents (2,3). Heparin-coated Palmaz-Schatz, Wiktor, Jostent, BX Velocity, and beStent have been investigated in clinical studies. All studies showed that heparin-coated stents are safe, even in high-risk lesions. When compared with balloon angioplasty, heparin-coated stents could significantly reduce the rate of subacute stent thrombosis and the late restenosis. However, no significant difference of restenosis was observed between the heparin-coated stent and the bare stent control. Drug-eluting thromboresistant stents Drug-eluting stents to reduce thrombotic complication have also been evaluated (Table 2). It is known that a final common pathway for platelet aggregation exists. Platelet aggregation is 21 Stent-mediated local drug delivery Yanming Huang, Lan Wang, and Ivan De Scheerder 1180 Chap21 3/14/07 11:30 AM Page 249 [...]... — — Self-designed PFM-P 75 Pig coronary art MP Dipcoating: 10– 15 µg in 5% (g/g) 20– 25 µg in 10% (g/g) Spraycoating PFM-P 75 Yes PFM-P 75 Yes 10– 15 µg in 5% (g/g) 20– 25 µg in 10% (g/g) PFM-P 75 No PFM-P 75 No In vitro studies Swanson (93) In vivo studies 1996 De Scheerder (18) 2000 100– 150 µg in 9% (g/g) 400– 450 µg in 33% (g/g) 700–1000 µg in 50 % (g/g) De Scheerder (18) 2000 Self-designed PFM-P 75 Pig coronary... AM Page 2 65 References 147 148 149 150 151 152 153 154 155 156 157 158 159 160 Ardissino D, Cavallini C, Bramucci E, et al Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries: a randomized trial JAMA 2004; 292(22):2727–2734 Hoye A, Tanabe K, Lemos PA, et al Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic... Heparin coating of endovascular stents decreases subacute thrombosis in a rabbit model Circulation 1992; 86(suppl):I186 Stratienko A, Zhu D, Lambert C, et al Improved thromboresistance of heparin coated Palmaz-Schatz coronary stents in an animal model [abstr] Circulation 1993; 88:I 59 6 1180 Chap21 3/14/07 262 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 11:30 AM Page 262 Stent-mediated local... compatibility of poly (styrene-b-isobutylene-b-styrene) The short- and long-term vascular compatibility of SIBS was examined in the porcine coronary model in an extensive portfolio of studies Histomorphometric comparisons for the CH3 H2 C CH3 H2 C H2 C CH3 H2 C X CH CH3 CH3 Figure 5 (See color plate.) Strut-associated inflammation in response to the polyethylene-co-vinyl acetate — poly-nbutyl methacrylate... Experimental study of Mytrolimus-eluting stents on preventing restenosis in porcine coronary model Zhonghua Xin Xue Guan Bing Za Zhi 20 05; 33(6) :56 1 56 4 Uurto I, Mikkonen J, Parkkinen J, et al Drug-eluting biodegradable poly-D/L-lactic acid vascular stents: an experimental pilot study J Endovasc Ther 20 05; 12(3):371–379 Collingwood R, Gibson L, Sedlik S, et al Stent-based delivery of ABT -5 7 8 via a phosphorylcholine... coronary art Ibuprofen Valsartan De Scheerder (18) 2000 Self-designed PFM-P 75 Pig coronary art Trapidil 92 µg in 10% (g/g) PFM-P 75 No Rogers (104) 2000 NIR NA Pig coronary art Paclitaxel NA Bare Yes Carter (1 05) 2000 NA NA Pig coronary art Sirolimus NA Bare polymer Yes Yes (Continued ) 1180 Chap21 3/14/07 11:30 AM Page 255 Drug-eluting stents to decrease neointimal hyperplasia Table 3 255 Drug-eluting stents... Giessen (52 ) 1994 P-S NA Pig coronary art Bare stent Yes No Jeong (53 ) 19 95 Wallstent NA Pig carotid art Bare stent Yes — Sheth (54 ) 19 95 Harts SPUU-PEO Rabbit carotid art Bare stent Yes — Chronos (55 ) 19 95 Cordis Hepamed Baboon carotid Bare stent Yes Yes Wilczek (56 ) 1996 Copper PUR Pig coronary art Bare stent Yes No Gao (57 ) 1996 Biodegradable CL ϩ LA Pig carotid art — — — Hardhammar (1) 1996 P-S Carmeda... Gerckens U, Muller R, Grube E Long-term evaluation of paclitaxel-coated stents for treatment of native coronary lesions First results of both the clinical and angiographic 18 month follow-up of TAXUS I Z Kardiol 2003; 92(10):8 25 832 Colombo A, Drzewiecki J, Banning A, et al Randomized study to assess the effectiveness of slow- and moderaterelease polymer-based paclitaxel-eluting stents for coronary artery... evaluation of c7E3-Fab (ReoPro) eluting polymer-coated coronary stents Cardiovasc Res 2000; 46(3) :58 5 59 4 Baron JH, Aggrwal RK, Azrin MA, et al Development of c7E3 Fab (abciximab) eluting stents for local drug delivery: effect of 1180 Chap21 3/14/07 11:30 AM Page 263 References 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 sterilization and storage [abstr] Circulation 1998; 98(17 suppl):I 855 Lahann J,... 20 05; 66(4) :54 1 54 6 Nakamura M, Wada M, Hara H, et al Angiographic and clinical outcomes of a pharmacokinetic study of sirolimus-eluting stents: lesson from restenosis cases Circ J 20 05; 69(10): 1196–1201 Airoldi F, Di Mario C, Ribichini F, et al 17-beta-estradiol eluting stent versus phosphorylcholine-coated stent for the treatment of native coronary artery disease Am J Cardiol 20 05; 96 (5) :664–667 . µg in 50 % (g/g) De Scheerder (18) 2000 Self-designed PFM-P 75 Pig coronary Ibuprofen 10– 15 µg PFM-P 75 No art in 5% (g/g) Valsartan 20– 25 µg PFM-P 75 No in 10% (g/g) De Scheerder (18) 2000 Self-designed. Scheerder (18) 2000 Self-designed PFM-P 75 Pig coronary MP Dipcoating: PFM-P 75 Yes art 10– 15 µg in 5% (g/g) 20– 25 µg in 10% (g/g) Spraycoating PFM-P 75 Yes 100– 150 µg in 9% (g/g) 400– 450 µg in 33% (g/g) 700–1000. form (50 0 mg or 2 g in sterile, lyophilized form). DFO mesylate is a white powder, freely soluble in water. DFO mesylate is N- [ 5- [ 3-[ ( 5- aminopentyl)hydroxycarbamoyl]propionamido] pentyl ]-3 -[ [ 5- ( N-hydroxyacetamido)pentyl]carbamoyl] pro-pionohydroxamic

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