Intermittent claudication pentoxifylline

Pentoxifylline (oxipentifylline) is a methylxanthine that antagonizes the vasoconstrictor effects of catecholamines and increases cyclic AMP concentrations, causing smooth muscle to relax. It has also been claimed to correct impaired microcirculation, by improving various factors that disturb blood rheology, and to reduce the generation of toxic free radicals from leukocytes during ischemic leg exercise in patients with intermittent claudication. Pentoxifylline has been used to suppress overproduction of tumor necrosis factor alfa in conditions such as falciparum malaria and rheumatoid arthritis and in transplant recipients, with varied success. 

Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. However, no evidence suggests that this therapy is superior to exercise conditioning. 

Oral 400 mg tablets and controlled-release tablets Note Pentoxifylline is labeled for use in intermittent claudication only. 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

Note Pentoxifylline is labeled for use in intermittent claudication only. 

Inhibitors) may be involved. A meta-analysis suggested that ginkgo was more effective than placebo and possibly comparable to pentoxifylline (Chapter 20 Drugs Used in Asthma) in relieving symptoms of intermittent claudication. 

Mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity (75). The recommended dose of pentoxifylline is 400 mg three times daily with meals. Pentoxifylline causes a marginal but statistically significant improvement in pain-free and maximal walking distance (a net benefit of 44 m in the maximal distance walked on a treadmill (95% Cl, 0 14 to 0 74) based on meta-analyses of randomized, placebo-controlled, double-blind clinical trials (76). At the same time pentoxifylline does not increase the ABI at rest or after exercise (56). Pentoxifylline may be used to treat patients with intermittent claudication however, it is likely to be of marginal clinical importance (56,77). Medical therapies... 

Girolami B, Bemardi E, Prins MH, etal. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl a meta-analysis. Arch Intern Med 1999 ... 

Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline meta-analysis of randomized controlled trials. CMAJ 1996 155 1053-1059. 

Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, Forbes WP, Strandness DE Jr. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000 109(7) 523-30. 

Ginkgo biloba has become popular bccau.se of its putative abilities to increase peripheral and cerebral circulation. ITic herb is called an adaptogen, a drug that helps persons handle stress. In the periphery, the hertj has been compared to pentoxifylline. If the properties arc true, the herb could be used for intermittent claudication. If cerebral blood flow can be increased with Ginkgo biloba. the herb might be useful... 

Ernst E. Pentoxifylline for intermittent claudication. A critical review. Angiology 1994 45 339-345. 

Pentoxifylline (400 mg t.i.d. p.o. with meals) is indicated in the treatment of intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. 

D. Clinical Use The major clinical indication for the use of methylxanthines is asthma theophylline is the most important methylxanthine in clinical use. Another methylxanthine derivative, pentoxifylline, is promoted as a remedy for intermittent claudication this effect is said to result from decreased viscosity of the blood. Of course, the nonmedical use of the methylxanthines in coffee, tea, and cocoa is far greater, in total quantities consumed, than the medical uses of the drugs. 

Several prospective randomized trials have reported that cilostazol improves walking distance in patients with intermittent claudication by 40 to 50%, compared to placebo after 12 to 24 weeks of treatment (20,21). One of these placebo-controlled trials evaluated both pentoxifylline and cilostazol (17). Pentoxifylline demonstrated no benefit in either onset of claudication or absolute claudication distance as compared to placebo. Cilostazol, however, significantly improved both distances compared to placebo (17). A prevalent side effect of cilostazol is headache. Transient diarrhea, palpitations, and dizziness have also been reported. The FDA has issued a warning regarding the use of cilostazol in patients with congestive heart failure, because of the increased possibility of sudden cardiac death observed with other forms of diesterase type III inhibitors. Thus, it has become routine practice to assess cardiac function clinically and echocardiographically prior to initiating therapy with cilostazol for claudication, and periodically thereafter. As a result of the modest vasodilatation, heart rate may increase by a mean of 5.1 and 7.4 beats per... 

Peter JM, Cutler BS, Lee BY, et al. Pentoxifylline efficacy in the treatment of intermittent claudication Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am Heart J 1982 104 66-72. 

Comparative studies Studies of prostanoids in intermittent claudication have yielded inconsistent results. In a multicenter comparison of three doses of oral iloprost, pentoxifylline, and placebo, conducted in 1998-1999 but published only in 2008, oral iloprost did not improve exercise performance or quality of Ufe pi "]. Serious adverse events did not differ among the groups and neither did any specific cardiovascular events. However, oral iloprost was poorly tolerated and therapy was often interrupted because of headache, flushing, nausea, or diarrhea. 

---