Pentoxifylline As Adjunctive Therapy in Leg Ulcer Management

• Pentoxifylline as adjunctive therapy in leg ulcer management

STEVEN A. BRENMAN, DO

Refractory or recurring leg ul- (Key words: Leg ulcers, pentoxifylline, cers typically signify the presence of im- wound care, microcirculation, venous ul- paired venous or arterial microcirculation cers, arterial ulcers) (or both). A current hypothesis suggests that local oxygen and nutrient deficits oc- Leg ulcers are a frequent cause of patient cur because capillary lumens narrow and discomfort and morbidity. Of more signifi- become permeable to fibrinogen and pro- cance, inadequate healing can lead to ulcer re- teins by activated white blood cells and currence, infection, and partial limb amputa- inadequate fibrinolysis. As a result, the tion. Leg ulcers are associated with ischemic deposition of a relatively impermeable per- disease and occur most frequently in the eld- ivascular fibrin sheath occurs, prevent- erly; the obese; and the diabetic; and in pa- ing adequate delivery of oxygen and nutri- tients with peripheral vascular disease, a his- ents. Therapy should therefore aim at re- tory of deep vein thrombosis, or vasculitis.1-4 versing these deficits and improving Ulcers also occur secondary to infection, ma- wound healing. Pentoxifylline (Trental), lignant disease, anemia, and trauma. A par- used in combination with local wound ticularly refractory type of ulcer develops in care and appropriate antibiotic therapy, patients with chronic venous insufficiency or has been successful in significantly im- venous hypertension and inadequate arterial proving the healing of refractory leg ul- circulation.5 cers. Pentoxifylline can reverse the abnor- Each year in the United States, 35,000 or mal function of white and red blood cells more diabetic patients require lower limb am- and platelets, as well as reduce blood vis- putation because of leg ulcers, a rate 15 times cosity and vascular permeability. The that of the nondiabetic population. Lower ex- mechanisms of action of pentoxifylline are tremity ulcers occur in patients with diabetes described in light of current hypotheses of long-standing duration (for example, 20 pertaining to leg ulcer development. Also years) as a consequence of the extensive pe- discussed are nine cases in which pentoxi- ripheral vascular, immunologic, and neuropa- fylline, when added to previously unsuc- thic diseases that become complications of dia- cessful local wound care, either improved betes.4,6 or healed the refractory ulcers. Leg ulcers develop as a result of inadequate oxygen and substrate delivery to, and removal The author has no commercial or proprietary interest in pentoxifylline, nor does he have any financial inter- of waste from, the skin and deeper tissues. How- est (as consultant, reviewer, or evaluator) in pentoxifyl- ever, the precise cause of, and optimal treat- line. ment for, many leg ulcers remains elusive. Em- Reprint requests to Steven Brenman, DO, West Side Skin Clinic, 2465 S Downing St, Suite 107, Denver, CO piric approaches that typically include local 80210-5886. debridement, topical modes of therapy, and an-

Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 677 tibiotics have not been universally effective.7 tension and preexisting arterial occlusive dis- Pentoxifylline (Trental), with its ability to ease. In an epidemiologic study that evaluated reduce hypercoagulability and blood viscosity, leg ulcers in 357 patients in England, 38% of has been used successfully in leg ulcer man- the patients had evidence of deep vein involve- agement.8-1° Treatment regimens incorporat- ment, 43% had superficial vein incompetence, ing pentoxifylline with local wound manage- and 10% had no venous or arterial disease, as ment produced ulcer healing rates of 60% to measured by ultrasound and refilling time.2 88% in a total of 850 patients who participated Ischemia was present in 70% of the patients in several open-labeled studies. 3-11 In addition, with intermittent claudication and in 31% of the results of two double-blind, placebo-con- the patients overall. trolled studies demonstrated that pentoxifyl- A recent theory suggests that white blood line, added to previously unsuccessful local cells (WBCs) (including neutrophils and to a care, healed or significantly improved 86% and lesser extent monocytes, lymphocytes, and baso- 75% of the ulcers, respectively. 8,10 In this arti- phils) may account for at least part of the tro- cle, I discuss various causes of leg ulcers, as phic skin and vascular flow changes associated well as the role of pentoxifylline in leg ulcer with venous ulcers (Figure ).5,1314 Venous hy- management, by relating my experience in pertension may reduce capillary flow, allow- treating nine patients with therapy-resistant ing WBCs to accumulate at the border of the leg ulcers. capillary lumen. Because most WBCs, such as neutrophils and monocytes, are significantly Hypothesis regarding the causes of leg larger than red blood cells (RBCs) and 1000 ulcers times stiffer, lumen resistance and blood vis- The pathophysiology of leg ulcers has been of cosity increase.5 interest for at least 2000 years. 12 In that time, Moreover, when the patient stands, arterial various theories have emphasized the role and venous hydrostatic pressures, as well as played in the evolution of leg ulcers by arte- capillary resistance, continue to increase, fur- rial insufficiency or hypercoagulability versus ther reducing capillary flow. The vessel endo- venous stasis, elevated venous pressure, ex- thelium becomes more permeable as aggre- cessive capillary permeability, and inflamma- gated WBCs release their toxic oxygen tion. Consequently, lower limb ulcers have metabolites and proteolytic enzymes such as been broadly categorized as either arterial or peroxiddse. Fluid, WBCs, fibrinogen, throm- venous, although many elderly and diabetic boxane, and other proteins leak through the patients, as well as patients with refractory capillary walls, causing edema, local tissue dam- leg ulcers, experience a combination of arte- age, and fibrin deposition. 5,12 Platelet aggre- rial and venous abnormalities. Recent hypothe- gation, RBC and WBC aggregation, and blood ses for ulcer development have evolved based viscosity continue to increase, along with the on these two categories. size of the pericapillary fibrin sheath and in- tracapillary resistance. Blood is shunted away Venous ulcers from the capillaries with high resistance, and Venous ulcers account for 81% or more of all ischemic tissue changes are exacerbated. As leg ulcers. 1,2 These ulcers are typically found the rigid fibrin sheath thickens, diffusion of over the medial malleolus with a margin that oxygen and nutrients becomes impaired and is usually less well defined than that of arte- the surrounding tissues undergo fibrosis. Ne- rial ulcers. Necrotic and eczematous changes crotic regions also form and may eventually may be present, and the lower leg may be ede- develop into an ulcer. matous with a papillomatous appearance. Four recent studies lend support to the hy- Patients with venous ulcers may have a his- pothesis that WBCs are intimately involved tory of deep vein thrombosis, familial venous with venous ulceration. In 1982, Browse and valve incompetence, ischemic vascular disease, Bernard12 reported the accumulation of peri- peripheral vascular disease, or venous hyper- capillary fibrin deposition in ulcerated regions

678 • JAOA • Vol 91 • No 7 • July 1991 Clinical practice • Brenman in patients with postphlebitic venous insufficiency. Soon afterward, Schmalzer and Chien15 found that one polymorphonuclear cell blocked Insult capillary blood flow as effectively as 700 RBCs Thrombosis in vitro. Recent work by Thomas and col- Venous obstruction leagues 15 demonstrated that 24% more WBCs Familial incompetent values became trapped in the interstitial fluid of the Immune complex/vasospastic disorder feet of ten sitting patients with venous hypertension as compared with ten sitting normal 1 subjects. Red blood cells did not become trapped to the same degree in either group. 1, Capillary flow rate T Venous pressure (with standing) Once the leg was elevated, WBCs were no longer trapped. Nash and colleagues 14 provided additional support to this hypothesis when they observed T White blood cell capillary adherence that WBCs from the arms of nine patients who T Hypercoagulable state required leg amputation had a significantly T Blood viscosity slower flow rate, or lower deformability rate, than WBCs isolated from ten control patients (P < .01). Moreover, the unfractionated WBCs obtained from the legs of the patients requir- T Endothelial damage ing amputation were significantly slower than those from the arms of the same patients. Once the amputation was completed, WBC flow rates increased and were not significantly dif- T Vascular permeability ferent from those of control subjects. 14 These studies therefore suggest that poor capillary V perfusion leads to the trapping of WBCs in in- Perivascular and intravascular terstitial fluid. This causes endothelial dam- fibrin/protein sheath forms age and the leakage of fluid and fibrinogen as well as proteolytic enzymes and inflammatory proteins. As an edematous, fibrous pericapillary sheath forms, tissue perfusion is re- Oxygen/nutrient delivery duced and venous ulcers form. Waste removal Venous ulcers may also occur in patients with occlusive arterial disease. These types of ulcers are frequently refractory to local treatments because of the added reduction in blood Tissue ischemia and oxygen supply. Refractory ulcers occur Edema formation most frequently in the elderly, smokers with peripheral vascular disease, and patients with diabetes or hypertension. Ulcer Arterial ulcers In contrast to venous ulcers, arterial ulcers have a more defined boundary and tend to be Fibrosis of tissue more painful, particularly at night when the leg is elevated and vascular supply is reduced. Arterial ulcers occur most commonly in patients with vasculitis of the subcutaneous ar- Figure. Proposed etiology of a leg ulcer.13

Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 679 teries, atherosclerosis, preexisting peripheral response similar to that seen with venous ul- vascular disease, diabetes, or chronic collagen- ceration. vascular diseases such as rheumatoid arthritis. Diabetic patients with lower-extremity ul- Ulcer management cers pose a particularly challenging therapeu- The optimal treatment of leg ulcers has not tic dilemma because significant numbers may been well documented in carefully controlled have coexisting peripheral vascular and neu- studies because of the variability in ulcer pa- ropathic disease, plasma hypercoagulability, thology, size, and healing rates. However, ther- increased blood viscosity, and abnormal lipid apy aimed at correcting the underlying defi- profiles.4,16,17 The ulcers may be arterial and cits and promoting granulation tissue should venous in nature, prone to infection because improve ulcer healing, as well as the pain and of their poor vascular supply and altered nu- poor quality of life of patients with leg ulcers. tritional status, and resistant to traditional Typical ulcer management focuses on the fol- modes of local therapy. lowing principles: restoring blood supply to the Arterial ulcers also frequently occur in pa- ulcer; keeping the wound clean and free of in- tients with necrobiosis lipoidica diabeticorum fection; promoting granulation tissue and or livedo vasculitis. Necrobiosis lipoidica dia- wound closure; and improving the nutritional beticorum is a degenerative chronic disease of status and concurrent conditions of the patient the dermal connective tissue strongly associ- predisposed to ulcer formation. ated with diabetes mellitus and most commonly affecting the anterior tibial region. The Local and systemic adjunctive modes of necrobiotic skin lesions may occur because en- therapy hanced platelet aggregation and adhesiveness The benefits and deficiencies of local and sys- and microangiopathy lead to local ischemia temic modes of therapy have been reviewed and a granulomatous reaction.18 extensively. 1,7 These reviews reveal that pa- Livedo vasculitis, a disease similar to atro- tients with venous leg ulcers typically have phic blanche, may occur as an idiopathic or edema, pigmentation changes, and incompe- symptomatic disease.9 The idiopathic variety tent venous valves in the lower limbs, as well occurs seasonally; in women, diffuse symmet- as recurrent, necrotic or bacteria-laden, ede- ric lesions or plaques develop on the lower legs matous, inflamed lesions. Necrotic tissue or yel- which eventually ulcerate. The symptomatic low exudate should be removed by debride- variety occurs in patients with changes in ment or wet dressings and local proteolytic en- blood viscosity or diseases of the blood vessel zymes such as fibrinolysin or desoxyribonu- wall such as rheumatic fever or arteriosclero- clease. sis. The typical patient with livedo vasculitis Local edema and swelling can be reduced is a woman in whom painful recurrent white with exercise, leg elevation, a compression ban- ulcers develop in response to a poor blood sup- dage, and systemic injections of corticosteroids ply caused by middermal vessels with thick such as triamcinolone acetonide or dex- hyalinized walls and narrow lumens.9 amethasone. Topical antibiotics or antiseptics The primary cause of arterial ulcers is the (for example, hydrogen peroxide or silver ni- lack of adequate blood supply. Local arterial trate) may be needed to prevent bacterial vessels, narrowed by atherosclerotic plaque or growth, particularly when dressings cannot be immune complex deposition, may undergo vaso- changed frequently. If a wound infection is spasm. This vasospasm reduces arterial blood suspected, an appropriate antibiotic should be flow, increases blood viscosity, and increases administered until culture and sensitivity re- the coagulability of the blood." Local hypoxia sults are available. and metabolic imbalances cause RBCs to be- Arterial ulcers are not treated with compres- come rigid, which impairs their passage sion bandages or leg elevation because these through capillaries and causes local tissue ne- measures reduce blood supply and enhance crosis. This necrosis heralds an inflammatory pain. The goal of therapy for arterial ulcers

680 • JAOA • Vol 91 • No 7 • July 1991 Clinical practice • Brenman Table 1 Relative Order of Onset of the Pharmacologic Effects of Pentoxifylline2223

Pharmacologic effect

Reduced blood Reduced Anti-inflammatory/ Response viscosity hypercoagulability antifibrotic

Immediate (within 48 h) 4, Platelet aggregation i.Platelet aggregation 1 Neutrophil direct migration TWBC flow rate Tissue plasminogen activator ,WBC hyperreactivity Fibinolysis 1Tumor necrosis factor, lAntiplasmin .1,0ther cytokines Delayed (within 12 wk) 1RBC aggregation 4. Fibrinogen TRBC deformability

I = increased; 1 = decreased; WBC — white blood cell; RBC = red blood cell. is to reverse the underlying cause of the im- ble 1), it acts synergistically with local treat- peded blood flow while reducing hypercoagu- ments to heal or improve therapy-resistant ve- lability and blood viscosity. Antiplatelet nous or painful arterial ulcers of various- agents (for example, aspirin or dipyridamole) causes.38-1121 and fibrinolytic agents (for example, minidose heparin sodium or dextran 40) have been used Mechanism of pentoxifylline early in therapy to reverse the underlying Data from two late-1980s studies2223 reveal causes of necrobiosis lipoidica diabeticorum that neutrophil activity is exquisitely sensi- and livedo vasculitis with varying rates of suc- tive to pentoxifylline. The drug is able to re- cess depending on the duration of the ulcers.9,18 duce neutrophil aggregation and adherence to In one open-labeled trial, aspirin (80 mg daily) the endothelium, as well as improve neutro- and dipyridamole (75 mg three times daily) phil migration and deformability within hours healed all seven patients necrobiotic ulcers of achieving local micromolar concentrations. within 2 to 4 weeks. However, no change oc- Pentoxifylline may also block the anti-in- curred in the fully established, older ulcers.18 flammatory effect of various cytokines, which Analgesics also may be required to reduce diminishes the magnitude of the vascular re- pain. sponse in diseases such as atrophie blanche Hyperbaric oxygen treatments may improve or arthritis.924 In contrast to antiplatelet ulcer healing in patients with vasculitis or pe- modes of therapy that irreversibly alter plate- ripheral vascular disease. Hyperbaric oxygen let coagulability, pentoxifylline improves the may act by closing arteriovenous shunts, in- hypercoagulable state by releasing tissue plas- creasing oxygen tension from 15 mm Hg (usu- minogen-activating factor and prostacyclin ally found in ischemic skin) to 30 to 40 mm without causing bleeding or a change in co- Hg, and by stimulating fibroblasts and neovas- agulation time.25 cularization of tissues. 19 However, hyperbaric Pentoxifylline also reduces RBC deformity oxygen has not been universally successful in and aggregation by increasing cellular concen- improving ulcer healing rates. 2° Additional re- trations of adenosine triphosphate and alter- search is needed to establish its role. ing calcium transport.26 Pentoxifylline, administered for 10 days preoperatively and for 10 Role of pentoxifylline days postoperatively, also significantly pro- Because pentoxifylline helps to correct blood longed skin flap survival in rats and swine by viscosity and the hypercoagulable state (Ta- reducing ischemia and blood viscosity, as well

Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 681 Table 2 Interventions and Outcomes in Nine Patients With Leg Ulcers Treated With Pentoxifylline and Other Adjunctive Treatment

Pentoxifylline Adjunctive Time interval Patient description regiment treatmenttt and outcomet

• Patient 1: 400 mg tid Wound debridement; Vigilon 3 wk: i ulcer size; 72-yr-old woman with and gauze kling wrap; granulation tissue ulcer of lower leg of 40 whirlpool 9 mo: Improved years duration; diabetes; hypertension; venous insufficiency

• Patient 2: 400 mg tid Erythromycin; vitamin B12 3-6 wk: 1 size; drainage; 86-yr-old woman with 6 wk: stop injection; DuoDERM healing ecchymosis; right calf 6 mo: start 6 mo: DuoDERM=Vigilon; 6 mo: Ulcer flare ulceration of 1 months add polymyxinflelfa; 6.5 mo: Better duration; CHF; osteo- erythromycin course 7 mo: Improving arthritis

• Patient 3: 400 mg tid Polymyxin/Telfa; butylated 3 wk: j size, swelling, pain, 83-yr-old-man with hydrocortisone cream; redness; I granulation stasis dermatitis; full- vitamin B 12 injection tissue thickness bilateral leg 4 mo: Erythromycin course; 4 mo: Ulcer flare; I stasis, ulcers for years; COPD; DuoDERM cultures PVD; CHF 6 mo: DuoDERM =elastic 5-6 mo: Better bandage wrap, add aspirin 7 mo: Add furosemide, prn 7 mo: swelling 11 mo: Add cloxacillin 11 mo: 1 ooze, ? infection 12 mo: 1 ooze, size/swelling 14 mo: All ulcers but one resolved • Patient 4: 400 mg tid Vitamin B 12 injection; 2 wk: I granulation tissue 61-yr-old woman with polymyxin/Telfa; elastic leg ulcers of 13 years bandage wrap duration; COPD; sinus- 5 wk: Add fluocinonide for 2 wk 5 wk: Reddened area itis; hypertension; atro- 2 mo: Add cephalexin, 500 mg 2 mo: New ulcer phie blanche bid; 1 dressing changes 2.5 mo: Change to ampicillin, 2.5 mo: I drainage nystatin 4 mo: Hyperbaric oxygen 4 mo: No improvement therapy; DuoDERM 4.5 mo: Improved Vigilon; dipyridamole 8 mo: Resolved

*CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; PVD = peripheral vascular disease. tbid = twice a day; tid = three times a day; qid = four times a day; god = every other day; prn = as needed. = increased; 1 = decreased; = switched to. as improving RBC deformity. By reducing plate- toxifylline (400 mg three times daily) reduces let, erythrocyte, and WBC aggregation and by shunt obstruction and significantly improves improving their deformability while reducing capillary flow, calf muscle and transcutane- fibrinogen, blood viscosity is reduced and tis- ous tissue oxygenation, exercise tolerance, and sue perfusion is enhanced. microcirculation in the feet of patients with The efficacy of pentoxifylline in treating ar- occlusive arterial disease, as measured by pho- terial ulcers may arise from its ability to re- toplethysmography, Doppler waveforms, xe- duce vascular resistance, dilate the arteries, non 131, or implanted electrodes.17,23,26,27 and improve RBC and WBC deformability and In summary, pentoxifylline is a useful ad- oxygen delivery. Several controlled in vitro junctive treatment for leg ulcers because it cor- and in vivo studies have documented that pen- rects WBC and RBC aggregation and deform-

682 • JAOA • Vol 91 • No 7 • July 1991 Clinical practice • Brenman Table 2 (continued) Interventions and Outcomes in Nine Patients With Leg Ulcers Treated With Pentoxifylline and Other Adjunctive Treatment

Pentoxifylline Adjunctive Time interval Patient description regiment treatmenttl and outcome

• Patient 5: 400 mg qid Aspirin qod; polymyxinfIelfa; 2 wk: r granulation 85-yr-old man with bi- 4 wk: 400 mg tid 10% silver nitrate; Vigilon; .l size, drainage lateral malleolus ulcers hyperbaric oxygen therapy for months; diabetes; 6 and 12 wk: Add vitamin 6 and 12 wk: Vasculitis vasculitis B12 injection flares 3 mo: Resolved; vasculitis flares

• Patient 6: 400 mg tid Aspirin qod; polymyxinfIelfa; 6 wk: Improved 68-yr-old man with sta- 10% silver nitrate sis dermatitis and bi- 4 mo: Add vitamin B12 4 mo: Flared lateral ankle ulcers of injection; furosemide; topical 8 mo: Resolved 10 days duration; zinc oxide/OpSite; polymyxin/ COPD; PVD; polycythe- len; Vigilon; elastic ban- mia, atrophie blanche dage wrap; erythromycin

• Patient 7: 400 mg qid 10% silver nitrate covered 3 wk: Ulcer resolved; 44-yr-old woman with with DuoDERM necrobiosis remains skin atrophy and foot/ leg ulcers of several months duration; PVD; necrobiosis lipoidica diabeticorum

• Patient 8: 400 mg tid 10% silver nitrate; polymyxin/ 2-3 wk:1 drainage, size, 70-yr-old woman with len; elastic bandage wrap pain stasis dermatitis and 2 mo: Resolved ankle ulcer of 8 months duration; PVD; hypertension

• Patient 9: 400 mg tid Erythromycin; vitamin B12 2 wk: Ulcer closure 78-yr-old man with bi- injection; polymyxin/Thlfa; 4 mo: Resolved lateral leg ulcers of 2 DuoDERM; Debrisan months duration; stasis dermatitis

*CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; PVD = peripheral vascular disease. tbid = twice a day; tid = three times a day; qid = four times a day; qod = every other day; prn = as needed. I: r = increased; 1 = decreased; = switched to. ity, improves oxygen delivery, and reduces to a local treatment regimen in open-labeled platelet aggregation as well as blood viscos- studies conducted in patients with conditions ity. Moreover, these beneficial effects are as diverse as previous deep venous thrombo- achieved without reducing blood pressure or sis, venous hypertension, diabetes, hyperten- causing bleeding, which would further reduce sion, peripheral vascular disease, vasculitis, perfusion pressure and superficial collateral livedo vasculitis, and atrophie blanche.3,9,11 blood flow.26 Pentoxifylline was well tolerated in all studies. The only side effects reported were gas- Clinical experience with pentoxifylline trointestinal in nature and included nausea, Pentoxifylline has produced ulcer healing or heartburn, and upset stomach. 8,21 Pentoxifyl- improvement rates of 61% to 88% when added line is also used to treat intermittent claudi-

Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 683 cation. In placebo-controlled clinical trials in fylline appeared to increase blood flow at the which patients received pentoxifylline for up ulcer site. Significant improvements in skin to 24 weeks, headache, dizziness, and tremor perfusion clearance occurred during exercise also were reported. However, the incidence (P < .05; as measured with technetium Tc 99m was less than that found with placebo treat- injected intradermally at the site of the ulcer), ment (1.2% vs 1.6%; 1.9% vs 3.1%; 0.3% vs and a significant reduction in mean fibrino- 0.8%, respectively). Also, although a cause- gen concentrations (P < .05) occurred after pen- effect relationship has not been established, toxifylline therapy. Venous patency and val- pentoxifylline may prolong the prothrombin vular competence did not change after the time. short pentoxifylline course. The ability of pentoxifylline to heal therapy- resistant leg ulcers of various etiologies and Experience with pentoxifylline in nine thicknesses was demonstrated most recently patients in two double-blind, randomized, placebo-con- Nine patients were recently referred to the trolled trials and one open-labeled study. 8,10,21 West Side Skin Clinic (Denver, Colo) because In the first double-blind, placebo-controlled of the failure of local therapy in healing leg trial,8 the leg ulcers, pain, and lymphostasis ulcers. In all nine patients, the major change of nine and 12 evaluable patients were healed initiated was either the addition of pentoxi- or improved with pentoxifylline administered fylline or an increase in the dose of pentoxi- in a dosage of 400 mg three times daily after fylline. Local therapy was continued (Table 2). meals for 6 months. In contrast, placebo ac- Wound debridement was done for patients counted for ulcer improvement in three to ten with excessive necrotic tissue. Frequent dress- evaluable patients. Improvement was rapid, ing changes and various wound protectants as- and initial improvements in ulcer size, pain, sisted in the healing process by removing ex- and lymphostasis were noted within 1 month udate. after initiation of therapy. The cause of the ulcers in these patients var- In the second placebo-controlled study, 1° the ied considerably (Table 2). Two had diabetes addition of pentoxifylline (400 mg three times mellitus and vascular insufficiency; four had daily) to previously unsuccessful topical ther- peripheral vascular disease (one of the four apy healed or significantly improved the leg also had atrophie blanche and one had necro- ulcers of 26 of 30 (87%) patients within 4 to biosis lipoidica diabeticorum); one had atro- 8 weeks of initiating therapy, while the addi- phie blanche; and one was an elderly patient tion of placebo to the same treatment plan im- with stasis dermatitis. proved 13 of 29 (45%) patients ulcers. 1° The difference in the healing rates between the two Ulcer healing groups was statistically significant (P < .01); Healing occurred in six (67%) of the nine pa- large, medium, and small ulcers were healed tients (patients 4 through 9). A significant im- with pentoxifylline therapy. The pentoxifylline- provement was noted in the remaining three treated patients also experienced a resolution patients. The dosage of pentoxifylline was usu- of the edema, pruritus, and pain at the ulcer ally 400 mg three times daily. It was increased site. to four times daily in two patients who had In an open-labeled study,21 ten patients (five received pentoxifylline previously with no bene- men, five women; mean age, 56.8 ± 7.1 years) fit (patients 5 and 7). Once the dose of pen- with a history of lower limb venous ulcers due toxifylline was increased and appropriate lo- to venous incompetence were subjects. Eight cal therapy continued, the ulcer healed in pa- of the ten had a complete or substantial re- tient 7. duction in the leg ulcer surface area after 6 Patient 5, who had underlying vasculitis weeks of pentoxifylline therapy combined with and diabetes, required hyperbaric oxygen treat- the use of double elastic support stockings and ment in addition to the increased pentoxifyl- dressings. The authors reported that pentoxi- line dose to clear the ulcer and control the vas-

684 • JAOA • Vol 91 • No 7 • July 1991 Clinical practice • Brenman culitis. Hyperbaric oxygen treatment was also and improves oxygen delivery without caus- used in a patient with atrophie blanche (pa- ing bleeding or other significant adverse ef- tient 4) before the ulcer completely healed. Ne- fects. The results of two double-blind, placebo- miroff19 has demonstrated that the combina- controlled clinical studies show the synergis- tion of pentoxifylline and hyperbaric oxygen tic effect of adding pentoxifylline to appropri- improved skin graft survival in swine by 86% ate local therapy to heal arterial and venous as compared with control subjects and by 30% leg ulcers and reduce the associated symptoms to 39% as compared with either therapy alone. of pain, pruritus, and edema. The data regard- This improvement was thought to be related ing nine patients with leg ulcers of various eti- to synergistic effects between these treatment ologies presented here, along with data from modalities. other open-labeled studies, lend further sup- In three patients, ulcers recurred. Patient port to the use of this drug. Pentoxifylline 2 had discontinued pentoxifylline therapy af- should be considered for the treatment of ther- ter the initial ulcer healed. However, the new apy-resistant leg ulcers. ulcer healed within 2 weeks after reinstitu- tion of the drug in combination with continu- ous local adjunctive therapy. The remaining 1.Buxton PK: Leg ulcers. Br Med J two patients (patients 4 and 6) had atrophie 1987;295:1542-1545. 2. Cornwall JV, Dote CJ, Lewis JD: Leg ulcers: Epidemiology blanche, and their ulcers flared after 6 to 8 and aetiology. Br J Surg 1986;73:693-696. weeks of continued pentoxifylline plus local 3. Herger R: The significance of the microcirculation in the treat- therapy. Because optimal rheologic effects of ment of leg ulcers. Therapie Woche 1986;36:3818-3828. pentoxifylline may not be seen for up to 12 4. Levin ME, Sicard GA: Evaluating and treating diabetic peripheral vascular disease: Part I. Clin Diabetes 1987;34:62-70. weeks, the relatively short duration of ther- 5. Thomas PRS, Nash GB, Dormandy JA: White cell accumula- apy may partially account for the ulcer flare.23 tion in dependent legs of patients with venous hypertension: Pentoxifylline added to appropriate but pre- A possible mechanism for trophic changes in the skin. Br Med J 1988;296:1693-1695. viously unsuccessful local and systemic thera- 6. Diabetic neuropathy, editorial. Lancet 1989;1:1113-1114. pies resulted in pronounced ulcer healing in 7. Ryan TJ: Current management of leg ulcers. Drugs these patients. The therapy was effective in 1985;30:461-468. diabetics, the elderly, and patients with colla- 8. Arenas R, Atoche C: Ulceras por complejo Vasculo-cutaneo de pierna: Seguridad y eficacia en el tratamiento con pentoxi- gen vascular disease and peripheral vascular filina. (Estudio doble ciego en 30 pacientes). Dermatologia Rev disease. However, the small number of pa- Mexicana Segunda Epoca 1988;32:34-38. tients in the study precludes any statistical 9. Ely H, Bard JW: Therapy of livedo vasculitis with pento- evaluation. All nine patients continue to re- xifylline. Cutis 1988;42:448-453. 10.Weitgasser H: The use of pentoxifylline (`Trental 400) in ceive long-term prophylactic pentoxifylline ther- the treatment of leg ulcers: Results of a double-blind trial. Phar- apy (400 mg three times daily) without sig- matherapeutica 1983;3(suppl 1):143-151. nificant adverse effects. 11.Ward A, Clissold SP: Pentoxifylline: A review of its phar- macodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 1987;34:50-97. Conclusions 12.Browse NL, Bernard KG: The cause of venous ulceration. Until the precise cause(s) of leg ulcers can be Lancet 1982;2:243-245. defined, the therapeutic approach will remain 13.Coleridge-Smith PD, Thomas P, Scurr JH, et al: Causes of venous ulceration: A new hypothesis. Br Med J 1988;296:1726- empiric. A recent hypothesis suggests that ve- 1727. nous ulcers may occur as a result of WBC hy- 14.Nash GB, Thomas PRS, Dormandy JA: Abnormal flow pro- peractivity that eventually leads to increased perties of white blood cells in patients with severe ischaemia endothelial permeability, increased blood vis- of the leg. Br Med J 1988;296:1699-1701. 15.Schmalzer EA, Chien S: Filterability of subpopulations of cosity, deposition of a relatively impermeable, leukocytes: Effect of pentoxifylline. Blood 1984;64:542-546. edematous fibrin sheath, and reduced oxygen 16.Corbin DOC, Young RJ, Morrison DC, et al: Blood flow in delivery to the surrounding tissues. the foot, polyneuropathy and foot ulceration in diabetes melli- Pentoxifylline improves WBC and RBC de- tus. Diabetologia 1987;30:468-473. 17.Schwartz RW, Logan NM, Johnson PJ, et al: Pentoxifylline formity; reduces WBC, RBC, and platelet ag- increases extremity blood flow in diabetic atherosclerotic pa- gregation; decreases fibrinogen concentrations; tients. Arch Surg 1989;124:434-437.

Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 685 18.Heng MCY, Song MK, Heng MK: Healing of necrobiotic and antithrombotic potential of pentoxifylline arentan: A re- ulcers with antiplatelet therapy: Correlation with plasma throm- view. Pharmatherapeutica 1988;5:159-169. boxane levels. Int J Dermatol 1989;28:195-197. 24.Sullivan GW, Carper HT, Novick WJ, et al: Inhibition of 19.Nemiroff PM: Synergistic effects of pentoxifylline and hy- the inflammatory action of interleukin-1 and tumor necrosis perbaric oxygen on skin flaps. Arch Otoiwyngol Head Neck Surg factor (alpha) on neutrophil function by pentoxifylline. Infect 1988;114:977-981. Immun 1988;56:1722-1729. 20.Leslie CA, Sapico FL, Ginunas VJ, et al: Randomized con- 25.Poggesi L, Scarti L, Boddi M, et al: Pentoxifylline treat- trolled trial of topical hyperbaric oxygen for treatment of dia- ment in patients with occlusive peripheral arterial disease: Cir- betic foot ulcers. Diabetes Care 1988;11:111-115. culatory changes and effects on prostaglandin synthesis. 21.Angelides NS, Weil von der Ahe CA: Effect of oral pento- Angiology 1985;36:628-637. xifylline therapy on venous lower extremity ulcers due to deep 26.Angelkort B, Pirnay D, Kiesewetter H, et al: Hemodilution venous incompetence. Angiology 1989;40:752-763. and pentoxifylline effects on muscle blood flow and blood fluid- 22.Ely H: White blood cells as mediators of hyperviscosity- ity in chronic arterial occlusive disease. Vasc Med 1983;1:150- induced tissue damage in neutrophilic vascular reactions: Ther- 158. apy with pentoxifylline. J Am Acad Dermatol 1989;20:677- 27.Roeren T, LeVeen RF, Nugent L: Photoplethysmographic 680. documentation of improved microcirculation after pentoxifyl- 23. Schonharting M, Musikie P, Muller R: The haemorheologic line therapy. Angiology 1988;39:929-933.

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