PHARMACOLOGIC MANAGEMENT OF PERIPHERAL VASCULAR DISEASE

NONOPERATIVE MANAGEMENT OF LOWER EXTREMITY ARTERIAL DISEASE, PART I

0039-6109/98 $8.00

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PHARMACOLOGIC MANAGEMENT OF PERIPHERAL VASCULAR DISEASE Dennis B. McNamara, PhD, Hunter C. Champion, PhD, and Philip J. Kadowitz, PhD

Although significant advances have been made in both interventional radiology and surgical management of peripheral vascular disease (PVD), many patients do not require intervention for occlusive disease of the lower-extremity arteries. Conservative regimens such as graded exercise, smoking cessation, and control of diabetes suffice for many claudication patients. However, recent estimations suggest that 70% of patients with intermittent claudication do not benefit from physical training. For this reason, a significant number of patients require pharmacologic therapy to assist in treatment of PVD. Examples of such patients are claudicants who are not disabled by their limitations but in whom conservative regimens are ineffective; patients with severely limiting claudication, rest pain, or trophic lesions who are not candidates for surgical or percutaneous intervention; and patients in whom an adjunct to interventional therapy is needed to improve overall reSUltS.12,22. 32, 34.46 The purpose of this article is to summarize the background for mechanisms of PVD as well as the available pharmacologic therapies designed to treat PVD. All these agents are aimed at affecting blood flow and delivery of oxygen at the microcirculatory level by various mechanisms. By targeting the cyclooxygenase/prostaglandin system, antiplatelet agents inhibit thromboxane formation and thereby enhance

From the Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana SURGICAL CLINICS OF NORTH AMERICA VOLUME 78 NUMBER 3 * WNE 1998

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the actions of prostacyclin (PGI,) released from the vascular endothelium. Hemorrheologics, such as pentoxifylline, improve microcirculatory flow by altering the membrane flexibility of blood elements and platelet aggregation. Moreover, future treatments may involve augmentation of the tissue renin-angiotensin system or inhibition of the endothelin system.'2,22 More recently, studies have assessed the potential for the use of direct vasodilator agents, such as novel nitric oxide donors, in the treatment of PVD. However, vasodilators generally do not relieve intermittent claudication because skeletal muscle circulation is controlled primarily by autoregulatory mechanisms. Thus, vasodilators do not generally increase blood flow beyond that produced by maximal exercise.49 Caution is required in the use of direct vasodilators because diversion of blood (steal) from diseased to nondiseased areas could be deleterious. PROSTAGLANDIN-BASED THERAPY Background

In patients with atherosclerotic lesions of the macrocirculation, the inflow of blood at the capillary level within a muscle group is impaired and may be inadequate to meet metabolic demands; thus, anaerobic metabolism is used, leading to a build-up of metabolic acids and resulting ischemic pain. The interplay of naturally occurring autacoids, such as PGI, and thromboxane A, (TXA,), determines the degree of resistance to blood flow and platelet aggregation within this environment and may further contribute to local ischemia. Metabolic acids, PGI,, and TXA, modulate cyclic adenosine monophosphate (CAMP)and adenosine triphosphate (ATP) levels within the vascular smooth muscle cell, erythrocyte membrane, and platelet, thereby modulating vascular tone, red blood cell (RBC) flexibility, and platelet activation.35,36 Cyclooxygenase Products

Recently, researchers have recognized that the endothelial lining of the blood vessel wall has functions other than that of a physical barrier between circulating blood and the subendothelial tissue elements. In 1976, it was reported that endothelium liberates arachidonic acid from membrane stores and produces PGI,. Arachidonic acid is stored in the phospholipids of cell walls (Fig. 1).On stimulation of the enzyme phospholipase A2,arachidonic acid is released. Free arachidonic acid can be converted to prostaglandin endoperoxide (PGH,) by the enzyme PGH synthase. PGH synthase exhibits two catalytic activities: cyclooxygenase that converts arachidonic acid to prostaglandin G, (PGG,), and peroxidase that converts PGG, to PGH,. Because the first metabolic step in

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Cell Membrane Phospholipid

Arachidonic Acid I

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+I

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Aspirin NSAIDS

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L

Peroxidase

l

PGD,

PGF,

TXAZ

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Figure 1. The cyclooxygenase cascade.

product formation is catalysis by cyclooxygenase, these products are called cyclooxygenase metabolite^.'^, 25 PGH, is a pivotal metabolite because it can be converted to a variety of products (see Fig. 1). Most cells contain PGH synthase17; therefore, the cyclooxygenase product formed by a cell depends on which of the PGH, metabolizing enzymes is present in that cell type. For example, PGI, is the major cyclooxygenase product of endothelial cells, whereas TXA, is the major cyclooxygenase product of platelets. Many drugs used in the treatment of PVD affect the pathway. PGI, is a potent vasodilator, inhibitor of platelet aggregation, and promoter of disaggregation of platelet aggregates, whereas TXA, is a potent vasoconstrictor and promoter of platelet aggregation. Therefore, conditions that favor increased TXA, formation over PGI, formation would be prothrombogenic. Endothelial damage (atherosclerosis, catheter-induced or bypass-induced) results in decreased localized PGI, for-

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mation with increased TXA, formation. After endothelial damage, the vascular smooth muscle cells can synthesize PGI, if they are not also damaged. However, their content of cyclooxygenase is less than that of endothelial cells36;therefore, less PGI, is produced, shifting the balance in the PGI,:TXA, ratio in favor of TXA,. PGI, formation is also decreased relative to the severity of atherosclerosis; however, this decrement has been reported to be focal in that it is confined to the area of plaque. The plaque itself can activate platelets, thus initiating aggregation in the areas where the local formation of PGI, is attenuated.,, 21* 45 Pharmacologic intervention can modulate cyclooxygenase product formation. Corticosteroids inhibit the release of arachidonic acid from cell membranes by inhibiting phospholipase activity. This therapeutic approach would be expected to reduce the synthesis of both PGI, and TXA,. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity. Aspirin irreversibly inhibits cyclooxygenase activity in both platelets and endothelial cells; however, the nucleated endothelial cell can synthesize new cyclooxygenase, whereas the enucleate platelet cannot. This differential effect on PGI, and TXA, formation has been used to therapeutic advantage in the treatment of ischemic heart disease. It should be noted that aspirin is an irreversible inhibitor of the cyclooxygenase enzyme, whereas other NSAIDs reversibly inhibit cyclooxygenase activity.50 It was discovered recently that different isoforms of cyclooxygenase (COX) exist. One is constitutively present in cells (COX-l), whereas the other is formed de novo (induced; COX-2) in human endothelial cells and monocytes in response to inflammatory cytokines such as interleukin-1. These different isozymes have been reported to be differentially inhibited by NSAIDs. Selective COX-2 inhibitors have been developed recently, and these compounds have been shown in preclinical laboratory investigations to inhibit COX-2-mediated inflammation without altering COX-1 expression in the gastrointestinal tract. It has been suggested that COX-2-selective inhibition might inhibit the synthesis of cyclooxygenase products associated with inflammation without suppressing those associated with the maintenance and modulation of normal physiology. The therapeutic efficacy of COX-2 inhibition in the management of PVD is currently ~ n c e r t a i n .38~ ~ , After the binding of PGI, to its receptor, adenylyl cyclase, the enzyme that catalyzes the conversion of ATP to CAMP,is activated (Fig. 2). Cyclic AMP activates CAMP-dependent protein kinase, which initiates a cascade of biochemical reactions resulting in the biologic response. In the vascular smooth muscle cell, synthesis of cAMP in response to PGI, results in vasorelaxation, whereas in the platelet the response is inhibition of platelet aggregation or promotion of disaggregation of previously aggregated platelets. Intracellular cAMP levels are decreased by the conversion of cAMP to 5’-adenosine monophosphate (5’-AMP) by the enzyme CAMP-dependent phosphodiesterase (see Fig. 2). This conversion attenuates the biologic response, because 5‘-AMP does not activate

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Platelet Activation Vessel Lumen

EC

7

f

Platelet Adenylyl Cyclase Activity

Cell Membrane Phospholipid

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Phospholipuse

Arachidonic Acid

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Figure 2. Effects of prostacyclin (PGI,) on vascular smooth muscle and platelets. = activation; - = inhibition; EC = endothelial cell; VSMC = vascular smooth muscle cell; PG = prostaglandin; AC = adenylyl cyclase; cAMP = cyclic adenosine monophosphate; ATP = adenosine triphosphate; [Caz+]i = intracellular calcium concentration.

CAMP-dependent protein kinase. Conversely, inhibition of CAMP-dependent phosphodiesterase activity would attenuate the breakdown of cAMP and prolong the biologic response.36,52 Methylxanthines, such as theophylline and pentoxifylline, have been shown to inhibit phosphodiesterase activity in vitro. It has been reported that therapeutic doses of methylxanthines do not produce high enough intracellular levels to inhibit phosphodiesterase. Recently, selective phosphodiesterase inhibitors have been developed that may prove useful in the management of PVD.36 Treatment with Prostaglandins and Related Therapeutics

PGI, and prostaglandin El (PGE,) cause vasodilation and inhibit platelet aggregation. Both are available in a clinically usable form. However, the only currently available route of administration is parenteral, which is not optimal in the long-term treatment of claudicants. However, PGI, or PGE, might be warranted in patients with rest pain, trophic

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lesions, or both, or in those who are not candidates for other interventions. In addition, agents that stimulate or inhibit the arachidonic pathway, such as inhibiting the formation of TXA,, preventing the binding of TXA, to its receptor, or stimulating native production of PGI,, might also prove beneficial in the treatment of PVD. Prostaglandin €, Intravenous PGE, has been available for the treatment of PVD in Europe since 1985. A multicenter trial in Germany reviewed the efficacy and tolerability of this compound in “routine” clinical usage.5 Intravenous PGE, was given to 211 patients and intra-arterial PGE to 218 patients, all of whom had severe PVD manifested by rest pain (stage 111), trophic lesions (stage IV), or both. Patients in both arms of the study received the drug daily for 4 weeks. Evaluation of therapy was by a pain score, amount of analgesics consumed, and reduction or changes in any ulcers or areas of necrosis. Nearly half the patients in each group experienced complete pain relief; another third had partial relief. Consumption of analgesics was also decreased significantly in both groups. Trophic lesions healed completely in 40% of both groups and partially in 19% with intra-arterial treatment and 11%with intravenous treatment. Twenty-three patients in the intra-arterial treatment group and 14 in the intravenous group eventually required amputation. Overall, the therapy was well tolerated; less than 10% had treatment stopped early because of adverse reactions (fewer in the intravenous group than in the intra-arterial group). This study demonstrates well that the efficacy of intravenous PGE, therapy is similar to that of intra-arterial treatment.5 Another study using intravenous PGE, compared its use to that of intravenous pentoxifylline in stage IV patients, the results of which strongly suggest that intravenous PGE, is beneficial in patients with severe PVD.50However, the required parenteral route of PGE, obviously has many drawbacks, including high cost and prolonged hospital stays. A recent study addressed the efficacy and safety of PGE, administered on an outpatient basis.I4 Two hundred and thirteen patients monitored received a 2-hour infusion of PGE, or placebo 5 days a week for 4 weeks, followed by a 4-week period of treatment with PGE, two times per week on an outpatient basis. The patients were followed for 3 months with no medication. The results of this study suggest that the regimen involving two treatments per week is as effective and safe as treatment five times per week for the outpatient treatment of intermittent claudication.I4 More recently, a study has been conducted using a PGE, prodrug, AS-013.7 AS-013 is an acylated, esterified PGE, derivative enclosed in lipid microspheres. This formulation provides several advantages over previous PGE, /microsphere preparations in that it has a higher solubility and reduced leakage, thus allowing better delivery of PGE, to the target site. The results from 80 patients with intermittent claudication

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(PAOD Fontaine Class 11) suggest that AS-013 can provide effective and acceptable treatment for patients with intermittent claudication. However, further studies are needed to determine the optimal dosing regimen and duration of clinical benefit. Prostacyclin Derivatives

A stable analogue of PGI,, iloprost, is a derivative of carbaprostacyclin and has been tested in patients with various stages of PVD. Oberender and colleagues40have conducted three placebo-controlled studies: one in 101 patients with trophic lesions due to PVD (study l), one in 109 patients with trophic lesions due to diabetic angiopathy (study 2), and one in 113 patients with rest pain due to either lesion (study 3). Sixty-two percent of all patients responded to iloprost treatment versus 17% of placebo-treated patients in study 1, 23% in study 2, and 43% in study 3. The differences between iloprost and placebo were significant in all patients. Of the patients with PVD who showed a response to the 2-week infusion, 88% had maintained a positive response at 1 year; however, 75% of those classified as nonresponders underwent amputation within 3 months. The results suggest a possible role for intravenous iloprost in patients with stage III/IV PVD.4O Other PGI, preparations are also available. Beraprost sodium is an orally active, stable PGI, analogue. A recent report demonstrates benefit in a patient with intermittent claudication due to spinal canal sten~sis.,~ However, controlled clinical trials are needed to better evaluate the effectiveness and safety of this PGI, analogue in the treatment of PVD. Another small study found that intravenous PGI, was ineffective in treating dialysis patients with claudication.@Therefore, despite a probable benefit for PGI, in patients with severe PVD, its use in patients with simple claudication is uncertain and requires further study.

Precautions Currently, the approved indication for PGE, therapy in the United States is for the prevention of NSAID-induced gastric mucosal The following observations were made in patients receiving oral PGE, therapy; they may or may not apply to intravenous therapy. PGE, and PGI, exhibit potent contractile activity on uterine smooth muscle; as such, caution is indicated in women of childbearing age, and these prostaglandins are contraindicated in pregnancy. They are also contraindicated in nursing mothers because they may cause significant diarrhea in nursing infants. PGE, and PGI, may interfere with the efficacy of NSAIDs in rheumatoid arthritis. Adverse reactions include diarrhea, nausea, flatulence, abdominal pain, headache, dyspepsia, vomiting, and c~nstipation.~~

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Prostacyclin Synthesis Stimulation

Another approach to the treatment of PVD is stimulation of the vascular endothelium to produce more PGI,. Although thrombolytic agents are not generally used in the chronic treatment of PVD, one such agent, defibrotide, has been reported to stimulate PGI, in addition to its thrornbolytic actions? One single-armed study reviewed the increase in walking distance and decrease of rest pain after infusion of defibr~tide.~ In 12 stage I1 patients, maximal walking distance was improved an average of 164%. In 10 stage I11 patients, rest pain was eliminated in 4. Photoplethysmography demonstrated increased flow in half the patients, although no data were given to correlate increased extremity blood flow with the observed clinical results. No change in ankle-brachial index (ABI) was found in either group. The second report was a randomized, single-blind study in 20 claudicant~.~~ These patients were treated daily as outpatients with intramuscular defibrotide or placebo for 3 months. They reported a significant increase in ABI (mean SE) (0.47 -+ 0.04 after treatment vs 0.43 k 0.05 before treatment) and a parallel increase in walking distance (407 f 54 meters after treatment vs 277 -t 42 before) in the treated group. A nonsignificant increase was noted in walking distance in the placebo group, and the ABI decreased. However, a direct comparison between the two groups was not done. There might be no difference between treatments if this comparison were made. Larger and better-designed studies are needed before defibrotide can be recommended in the treatment of PVD. NITRIC OXIDE-BASED THERAPY Background Another important endothelium-derived vasoactive factor is nitric oxide. It was first noted in 1980 that the presence of endothelium is obligatory for acetylcholine to produce relaxation in isolated vascular rings. The chemical nature of the mediator formed by the endothelium in response to acetylcholine activation of the muscarinic receptor was unknown, and it was named endothelium-derived relaxing factor (EDRF). In 1987, it was proposed that EDRF was the gas nitric 2H, 3y It is now recognized that the formation of nitric oxide from Larginine is catalyzed by nitric oxide synthase (Fig. 3). These observations led to a classification of drugs known as endothelium-dependent vasodilators (agonists that stimulate nitric oxide formation, e.g., acetylcholine).24,28, 79 As with cyclooxygenase, different isoforms of nitric oxide synthase are present. The constitutive as opposed to inducible isoform is present in the endothelium; it is thought to be stimulated by shear stress as well as circulating hormones and paracrine factors. Another isozyme is not constitutively present, but its formation can be induced in the vascular

PHARMACOLOGIC MANAGEMENT OF PERIPHERAL VASCULAR DISEASE PMN AdherenceIActivation

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Platelet Activation

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NO + L-Citrulline L

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Figure 3. Synthesis of nitric oxide (NO) and its effects on vascular smooth muscle (VSMC), platelet activation, and polymorphonuclear leukocyte (PMN) adherence/activation. + = activation; - = inhibition; EC = endothelial cell; ACh = acetylcholine; M = muscarinic receptor; cNOS = constitutive nitric oxide synthase; iNOS = inducible nitric oxide synthase; PLC = phospholipase c; DAG = diacylglycerol; IP, = inositol triphosphate; GC = guanylate cyclase; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; [Caz+]i = intracellular calcium concentration.

smooth muscle cell by factors such as interleukin-1 (endotoxin) or catheter injury. This inducible enzyme is not activated by circulating hormones or paracrine factors, but rather converts L-arginine to nitric oxide without agonist s t i m ~ l a t i o n28,. ~39~ ~ Like PG12, nitric oxide is a vasodilator and an inhibitor of platelet aggregation. Endothelial damage results in decreased formation of nitric oxide. Moreover, the neoendothelium that forms after catheter-induced vascular injury exhibits an attenuated formation of nitric oxide by the constitutive nitric oxide synthase, as evidenced by decreased relaxation 28, 39 to endothelium-dependent vasodilators such as acetylch~line.~~~ Pharmacologic modulation of nitric oxide formation is currently limited in scope. Angiopeptin, a somatostatin analogue, is reported to enhance nitric oxide formation of neoendothelium formed after catheter injury.30Heparin treatment has also been shown to augment acetylcholine-induced relaxation (nitric oxide formation) mediated by the neoen-

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dothelium formed after catheter injury3' Endothelium-dependent vasodilation is attenuated by low-density lipoprotein cholesterol." Conversely, oral administration of L-arginine decreased the surface area and reduced intimal thickness of atheromatous lesions in hypercholesterolemic rabbit aorta.13This treatment was associated with improved endothelium-dependent vasorelaxation. L-arginine administration intravenously has also been shown to increase acetylcholine-stimulatedhindlimb blood flow in hypercholesterolemic rabbit^.'^ Moreover, oral administration of L-arginine has been shown to attenuate intimal thickening after catheter injury.37This study has also showed that endogenous Larginine may have an important role in attenuating vascular remodeling.37More recently, we observed that co-administration of L-arginine with either felodipine or isradipine, dihydropyridine calcium channel antagonists, resulted in a loss of the attenuating effect on intimal thickening after catheter injury.' It is uncertain whether L-arginine therapy will be efficacious in humans. However, concurrent use of L-arginine with dihydropyridine calcium channel antagonists should be approached cautiously. Animal studies suggest that pharmacologic intervention may prove efficacious in augmenting nitric oxide formation.', 13, 37 They also suggest that L-arginine administration may be therapeutically beneficial in inhibiting vascular remodeling after injury and normalizing vascular reactivity after injury, and as an antiatherogenic agent. Nitric oxide binds to the heme moiety of soluble guanylyl cyclase, resulting in the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) (see Fig. 3). Cyclic GMP activates cGMP-dependent protein kinase, initiating a cascade of biochemical reactions that result in the biologic response. In vascular smooth muscle, synthesis of cGMP in response to nitric oxide results in vasorelaxation, but in the platelet cGMP inhibits platelet aggregation. Intracellular cGMP levels are decreased by the conversion of cGMP to 5'guanosine monophosphate (5'GMP) by the enzyme cGMP-dependent phosphodiesterase. This conversion attenuates the biologic response because 5'-GMP does not activate cGMP-dependent protein kinase. Conversely, inhibition of cGMP-dependent phosphodiesterase activity would prolong the biologic response. This effect could be therapeutically advantageous in view of the effect of L-arginine on the regression of atherosclerotic lesions, increased limb blood flow, and attenuation of vascular remodeling.24,28, 39 We suggest that perhaps concomitant treatment with L-arginine and a selective inhibitor of cGMP-dependent phosphodiesterase would produce a greater antiatherogenic effect as well as increased limb blood flow. Another class of agents is the nitric oxide-donating drugs, such as nitroglycerin and sodium nitroprusside, now known to induce vasodilation by directly releasing nitric oxide rather than by stimulating its formation from L-arginine. A drawback of use of nitroglycerin and sodium nitroprusside rests in the short duration of action of the compounds. Recently, nitric oxide donors have been developed with more prolonged durations of action and may prove useful in the treatment of

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PVD by providing a sustained increase in blood flow as well as offering an antithrombogenic activity.51

ANTIPLATELET THERAPY Antiplatelet agents are used in treating a wide variety of atherosclerotic conditions, such as prevention of stroke and modification of risk for myocardial infarction. Both PGI, and PGE, produce antiplatelet effects and were discussed previously. These drugs work through a variety of mechanisms that generally lead to inhibition of TXA, and, therefore, platelet aggregation. Their use in treatment of claudication and prevention of progression of extremity atherosclerosis has also been investigated.

lndobufen Indobufen, an NSAID that inhibits cyclooxygenase activity, has been used in two studies.6*48 One study indicated that indobufen treatment might be of some benefit6; however, the second study did not support this c o n c l ~ s i o nNeither .~~ of the studies evaluated the role that indobufen’s analgesic properties might have in their findings.6,48 A recent study comparing the effects of indobufen and pentoxifylline provides evidence suggesting that, although both treatments improved walking distance, the effect of indobufen was more p r o n o u n ~ e dIndobufen .~~ is an NSAID whose primary mechanism of action is thought to be inhibition of cyclooxygenase activity, thereby inhibiting the synthesis of TXA,, PGE,, and PGI,. Concomitant treatment with indobufen and PGE, could decrease the incidence of gastrointestinal adverse reactions associated with NSAID treatment as well as provide the ameliorating effects of PGE, and PGI, treatment, as discussed above.42

Ticlopidine Ticlopidine acts by irreversibly inhibiting adenosine 5’-diphosphate-stimulated fibrinogen binding to its platelet re~eptor.~, A multicenter, randomized, double-blind trial of 169 patients given either placebo or ticlopidine found that significantly more patients in the ticlopidine group (39 vs 29) increased their walking distance more than 50%.3 Both groups significantly increased pain-free and total walking distance as a whole, the ticlopidine group significantly more than the placebo group. However, no data were given comparing the actual distances walked; only the increase in distance walked was compared. Another interesting finding of this study is that more atherosclerotic events (cerebral or peripheral ischemia) occurred in the placebo group than in the ticlopidine group. In a smaller study of ticlopidine compared

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with aspirin and dipyridamole treatment, a significant decrease in plasma fibrinogen levels was associated with an increased walking distance in the ticlopidine-treated group. The aspirin/dipyridamole group had a nonsignificant decrease in fibrinogen levels; however, data regarding walking distances in these patients were not given.3 Another study randomized 296 patients into three treatment groups: ticlopidine; aspirin/dipyridamole; and xanthinol nicotinate, a vasodilator.I8An increase in both RBC filterability and ABI, as well as a decrease in platelet aggregation, was reported in both the ticlopidine and aspirin/ dipyridamole groups; however, no interdrug analyses were made and no information regarding the effect on claudication was given. Thus, although ticlopidine may have some beneficial effects in patients with PVD, its true efficacy, especially in the treatment of claudication, needs further clarification.ls Precautions

Ticlopidine is currently approved for use to reduce the risk of thromboembolic Its use for this indication is associated with a risk of neutropenic agranulocytosis, which may be life-threatening. Therefore, it should be used with caution and is contraindicated for therapy in the presence of neutropenia, thrombocytopenia, bleeding disorders (e.g., ulcer), and severe hepatic dysfunction. Little information is available on its use in renal disease, but dosage adjustment may be required.43 HEMORRHEOLOGIC AGENTS

Several drugs can cause alterations in the membrane characteristics of blood elements, thereby allowing for a smoother flow through the small capillary networks. The best known of these is pentoxifylline. Other agents purported to have this action include low-molecularweight dextran, naftidrofuryl, buflomedil, bencyclane, and fructose-1, 6diphosphate. Patients with PVD have decreased RBC deformability and blood filterability, and RBC flexibility is an important factor in blood viscosity. Hemorrheologic agents aim to improve this flexibility, thereby lowering the blood viscosity and improving flow. Pentoxifylline

The most widely studied and reported hemorrheologic drug is pentoxifylline, a methylxanthine derivative.l6*19, 23 The only drug approved by the Food and Drug Administration (FDA) for treatment of intermittent claudi~ation,4~ pentoxifylline improves RBC filterability in a

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dose-dependent fashion. In a study involving healthy male volunteers, this was not the result of an alteration in erythrocyte membrane lipids, and its exact mechanism of action is unknown.'O Improved leukocyte filterability and decreased formation of free radicals during ischemia have also been demonstrated when pentoxifylline was given to claudicants. These patients also exhibited improved recovery time of transcutaneous oxygen pressure (TCP,,) after ischemia compared with placebotreated controls.1° In a practice setting where patients must pay for their medications, all claudicants were prescribed pentoxifylline over an 18-month period. Initially, 130 patients were enrolled and were followed for an average of 9 months. Seventy-one percent of the patients had no perceived improvement, and 10% had only a short-lived benefit. Six percent stopped taking the drug because of side effects, and another 28% quit because of no perceived benefit and the high cost of the medication.,O In a similar study from a Veterans Administration Hospital where patients were given the drug at no cost, 31% reported improvement in walking distance; 48% discontinued the drug on their own, mainly because of side effects (13%) or lack of efficacy (23Y0).,~Another study compared the effects of aspirin and pentoxifylline in an elderly population. Whereas patients from both groups reported similar levels of pain, the pentoxifylline group reported a 60% farther walking distance than the aspirin Thus, pentoxifylline has a demonstrable benefit in some patients, but the mechanism to identify patients who will benefit most from pentoxifylline is not clear. However, its use as an adjunct to therapies of graded exercise and cessation of smoking may prove efficacious.

Precautions There have been reports of bleeding or prolonged prothrombin time for patients on pentoxifylline therapy.*, 29 Patients receiving concomitant therapy with anticoagulants or inhibitors of platelet aggregation should have more frequent monitoring of prothrombin times. Other patients at risk for hemorrhage (e.g., recent surgery, peptic ulcers) should have their bleeding times, hematocrit, or hemoglobin checked periodically. It should be used with caution in pregnancy and by nursing mothers. Adverse reactions reported by less than 2% of patients include angina/chest pain, dyspepsia, nausea, vomiting, dizziness, headache, and trem0r.4~ The reported symptoms of overdosage include hypotension, convulsions, somnolence, loss of consciousness, fever, agitation, and flushing. Treatment of overdosage includes activated charcoal, gastric lavage, and supportive measures directed at maintaining respiration and systemic blood pressure and controlling convulsions.

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Other Hemorrheologic Agents

Several other hemorrheologic agents have been used in the treatment of PVD, although their effects are not as well documented as those of pentoxifylline. Naftidrofuryl increased pain-free and maximal walking distance from baseline values in patients with intermittent claudication and those with more severe PVD.26Bencyclane was tested in a group of mild claudicants (average initial pain-free walking distance of 500 meters), and a significant average increase was found in pain-free walking distance.36Another agent, fructose-1,6-diphosphate, which increases RBC ATP, was found to decrease whole blood viscosity and RBC deformability3'jBuflomedil has both hemorrheologic and vasodilator properties, the mechanisms of which are poorly understood. In a small study of patients with varying degrees of PVD, a 7-day course of buflomedil increased basal TCP,, levels significantly in four patients with rest pain or trophic lesions and improved the half-recovery time to basal TCP,, levels in eight claudicants after ischemia.36 OTHER THERAPEUTIC TARGETS Vascular Wall Renin-Angiotensin System

A complete renin-angiotensin system is reportedly present in the vascular wall. Cultured endothelial and vascular smooth muscle cells synthesize renin, angiotensinogen, angiotensin I, angiotensin 11, and angiotensin 111. Receptors for angiotensin are present on vascular smooth muscle cells in various vascular beds, and angiotensin-converting enzyme (ACE) is present at the adventitial-medial junction and in the endothelium. The extent of the conversion of angiotensin I to angiotensin I1 is similar in control and de-endothelialized arteries. Because vascular formation of angiotensin I1 at the adventitial-medial border occurs adjacent to vascular noradrenergic nerves, it is thought that this conversion may have an important paracrine facilitatory role in regulating sympathetic function and vascular tone. As such, it has been suggested that attenuation of the activity of tissue in ACE rather than plasma ACE by ACE inhibitors is important for the antihypertensive effect of ACE inhibition. ACE inhibitors are efficacious in increasing peripheral blood flow in normotensive claudicants; this may represent inhibition of tissue ACE with subsequent decrease in sympathetic tone. However, more studies are indicated. It would be interesting to undertake a study of ACE inhibition concomitant with L-arginine administration, based on the effects of L-arginine admini~trati0n.l~ Endothelin

Endothelin is a 21-amino-acid peptide that exists as three isoforms in humans. Endothelin 1 (ET-1) is continuously formed by the endothe-

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lium by sequential cleavage and is an endothelium-derived contractile factor. Prepro ET-1, which contains 203 amino acids, is cleaved to pre ET-1; which, in turn, is cleaved to form ET-1, a 21-amino-acid peptide, which is then released from the endothelial cells. Big ET-1 and ET-1 are vasoconstrictors in the hindquarter vascular bed of the cat, but ET-1 is more potent. ET-1 has been shown in vitro to have a greater contractile effect on human saphenous vein than human gastroepiploic artery, and although it was a weaker vasoconstrictor than a stable analogue of TXA,, it was suggested that ET-1 could produce contraction or vasospasm in both vessels. Synthesis of prepro ET-1 is increased by thrombin, and this stimulated release has been reported to be attenuated by nitric oxide. ET-1 release from endothelial cells is also stimulated by angiotensin 11. Endothelin binds to a specific receptor, the expression of which in vascular smooth muscle can be downregulated by ET-1 or angiotensin 11.33

Thus, although the control of the synthesis and release of ET-1 is not fully understood, therapeutic modalities currently under investigation may modulate the synthesis and release of ET-1 (e.g., ACE inhibitors, L-arginine). Bosentan is a recently developed, orally active, ET-1 receptor antagonist shown to decrease systemic arterial pressure in patients with congestive heart failure, but the role of ET-1 in intermittent claudication and benefits of ET-1 receptor antagonism remain speculati~e.~~ MISCELLANEOUS AGENTS

Ketanserin Ketanserin is a 5-hydroxytryptamine2 (5-HT2)serotonergic receptor antagonist that also displays some alpha-adrenergic blocking properties, thereby antagonizing vasoconstriction, blocking 5-HT-induced platelet aggregation, and improving the hemorrheologic properties of blood.41 Its use is primarily as an antihypertensive, and it has also been used in treatment of Raynaud’s phenomenon. These properties have led to investigation of its use in the treatment of PVD. Although ketanserin is probably of no direct benefit in the treatment of claudication, it is safe to use in hypertensive patients because it preserves limb blood flow in the affected limbs and does not worsen symptoms, as do some other antihypertensive agents. Severe adverse reactions to the therapeutic use of ketanserin have not been documented, but minor side effects include dry mouth, nausea, dizziness, and ~ e d a t i o n . ~ ~ Vasodilating Substances Vasodilating agents have been used for many years in the treatment of PVD; however, despite anecdotal reports of success, the results of

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treatment with vasodilators in obstructive vascular conditions have generally not been good when evaluated objectively. It has been suggested that vasodilating agents such as ATP-sensitive potassium (KfATp)channel openers and nitric oxide donors may prove useful in the treatment of PVD.49,51 Because of the local vasodilating effect of ischemia, a potent stimulator of PGI, release, further vasodilation may be impossible within the ischemic muscle bed, and treatment with vasodilators that dilate nonischemic areas as well may, in fact, cause a steal phenomenon and worsen local ischemia. Drugs with other effects in addition to their vasodilating properties (e.g., PG derivatives and hemorrheologic agents) were discussed previously and may have some benefits. However, the efficacy of treatment with drugs that work primarily through vasodilating effects remains ~ n c e r t a i n . ~ ~ SUMMARY

Although our understanding of the pathophysiology of atherosclerosis and peripheral vascular disease continues to grow, we have yet to discover a medication that can safely and efficaciously be given to most claudicants that will alleviate their symptoms to prevent disease progression. Many patients with intermittent claudication improve or remain stable without therapy if they attempt to alter their risk factors (e.g., control of diabetes, smoking cessation, lowering of cholesterol levels). However, many require concomitant drug therapy to alleviate symptoms of PVD, and some require surgical intervention. Even with the recent advances in therapeutic development and the promise of agents currently in clinical trials, the questions of who to treat, when treatment should begin, and which agent to use remain uncertain.22

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