Peripheral Vascular Disease
Pentoxifylline is used for the symptomatic treatment of intermittent claudication associated with peripheral vascular disease (i.e., chronic occlusive arterial disease of the extremities). Although pentoxifylline may provide some improvement in function of the extremities and symptoms of the disease, management of intermittent claudication with the drug should not replace more definitive therapy for peripheral vascular disease such as smoking cessation, weight loss, exercise therapy, or surgical bypass or removal of arterial obstructions when indicated.
Intermittent claudication is a symptom complex that is associated with an inadequate arterial blood supply to contracting muscles and that occurs principally in patients with peripheral vascular disease in whom the supply of arterial blood is diminished during exercise. Symptoms of intermittent claudication include aching, cramping, tiredness, or tightness in the affected extremity(ies) and are exercise induced; symptoms never occur at rest or with weight bearing alone and are induced more quickly by an increased rate of exercise. A constant amount of exercise will usually gradually induce increased discomfort; however, a sudden progression of discomfort indicates acute occlusion of the main or collateral vessels. Symptoms of intermittent claudication generally are completely relieved in a few minutes following cessation of exercise.
Evidence from hemorrheologic studies indicates that blood flow is impaired in patients with various hematologic (e.g., polycythemia, multiple myeloma, sickle cell disease) and cardiovascular (e.g., acute myocardial infarction, hypertension, Raynaud's syndrome) diseases, and that, in addition to vascular components, blood flow also depends on blood viscosity and the coagulation system, including platelet function and coagulation factors in the blood. Hemorrheologic abnormalities, including increased erythrocyte and platelet aggregation and impaired erythrocyte flexibility, are generally present in patients with peripheral vascular disease and are associated with a secondary hyperviscosity syndrome, which correlates directly with the severity of vascular disease and tissue ischemia. Tissue hypoxia increases blood vessel wall permeability and intensifies the local influx of vasoactive substances and coagulation factors into the blood, which subsequently leads to increased local hemoconcentration and erythrocyte rigidity as a result of release of catabolites produced by anoxic parenchymal metabolism. These intravascular changes enhance intravascular coagulation and result in further impairment of blood flow in the already decompensated microcirculation in patients with peripheral vascular disease.
In patients with intermittent claudication, pentoxifylline therapy has been shown to provide some improvement in walking distance and duration as measured by standardized treadmill or walking distance testing. However, the efficacy of pentoxifylline compared with other forms of therapy (e.g., exercise) has not been elucidated. Results from well-designed, controlled clinical studies indicate that pentoxifylline is more effective than placebo in increasing initial (tolerable) and absolute (intolerable) claudication distances. Pentoxifylline also has been reported to produce greater reductions in severity and occurrence of paresthesia and trophic ulcers than does placebo; however, the drug does not appear to be more effective than placebo in relieving other symptoms associated with claudication such as cramping, tiredness, tightness, and pain during exercise.
Clinical evaluations of pentoxifylline in the management of intermittent claudication and in vitro studies have shown that pentoxifylline therapy increases erythrocyte flexibility, muscle oxygen pressure (PO2), and blood flow and decreases whole blood viscosity in patients with peripheral vascular disease. The results of these findings suggest that the efficacy of pentoxifylline in the management of intermittent claudication results from the drug's effects on improving blood flow via changes in erythrocyte flexibility and subsequent increase in tissue oxygenation.
Pentoxifylline has been used for the management of acute and chronic cerebrovascular insufficiency in a limited number of patients. Pentoxifylline therapy has improved regional and hemispheric cerebral blood flow, particularly in ischemic areas where microcirculation is impaired, and has been associated with measurable increases in oxygen and glucose supply, elimination or reduction of perivascular edema, and enhancement of cellular function in some patients with cerebrovascular insufficiency. Improvement in cerebral blood flow has been observed following acute or chronic and oral or IV administration of the drug. Clinical evaluation of patients receiving pentoxifylline indicates that the drug can improve psychopathologic symptoms of cerebrovascular insufficiency (e.g., those associated with aging, stroke, transient ischemic attacks), including memory loss, disorientation, constructional apraxia, impaired practical reasoning, motor impairment, and dizziness. In addition, pentoxifylline therapy has reduced the incidence of recurrence of transient ischemic attacks. Additional studies to determine the efficacy of pentoxifylline in patients with cerebrovascular insufficiency are currently under way.
Pentoxifylline has been used prophylactically in at least one patient for the management of sickle cell disease. The drug appeared to prevent sickle cell crises and related pain without reducing hemolysis, and there reportedly was a correlation between clinical improvement and improvement in microrrheologic parameters including normalization of erythrocyte flexibility. Additional studies to determine the role, if any, of pentoxifylline in the management of this disease are currently under way.
There is some evidence that pentoxifylline may have beneficial effects in patients with diabetes mellitus. The drug has improved hemorrheology in diabetic patients, and has reduced urinary albumin and total proteinexcretion and increased creatinine clearance in some diabetic patients, including a limited number with nephropathy. Subjective improvement in peripheral neuropathy also has been reported in a limited number of diabetic patients receiving the drug. In at least one patient, pentoxifylline therapy reportedly improved healing of cutaneous ulcers associated with necrobiosis lipoidica diabeticorum.
Pentoxifylline has been used IV in combination with dextran 40 and cortisone for the treatment of Bell's palsy (idiopathic facial paralysis). In a limited number of patients, this combination regimen has reportedly been more effective than cortisone alone or surgical facial nerve decompression as evidenced by an increased percentage of patients achieving complete recovery according to clinical and neurophysiologic (e.g., electromyographic) evaluation. Additional study to determine the efficacy, if any, of pentoxifylline alone or in combination with other drugs in the treatment of Bell's palsy is necessary.
Pentoxifylline has been used in a limited number of patients for the treatment of male fertility disorders, including asthenospermia and idiopathic oligospermia. Pentoxifylline has been reported to increase the duration of activity of ejaculated spermatozoa and, in one study, several males with asthenospermia successfully impregnated their wives during therapy with the drug. However, in another study comparing the effectiveness of pentoxifylline with that of placebo, clomiphene citrate, mesterolone, or testosterone rebound therapy for the treatment of idiopathic oligospermia, pentoxifylline therapy did not result in a clinically important increase in mean sperm count nor in successful pregnancy in the sexual partners. In this study, clinically important increases in mean sperm concentration and successful pregnancy only occurred in association with clomiphene citrate therapy. Further study is needed to adequately determine the role, if any, of pentoxifylline in the treatment of male fertility disorders.