Pentoxifylline: A drug with wide spectrum applications in dermatology
Pars Clinic, Rasht, Iran. firstname.lastname@example.org
Pentoxifylline (PTX) is a methylxanthine derivative with a variety of anti-inflammatory effects. Currently, PTX is approved by the Food and Drug Administration for the treatment of intermittent claudication, but studies have shown that it has a variety of physiological effects at the cellular level, which may be important in treating a diverse group of diseases.
Clinical applications of PTX in dermatology have been reviewed by Samlaska et al . More recent clinical indications in dermatology will be discussed following a brief review of its effects at cellular levels.
Effects of PTX on different cellules and molecules
Tumor Necrosis Factor-α (TNF-α) is a cytokine with a wide spectrum of activity which is predominantly produced by mononuclear cells. Increasing evidence has implicated TNF-α as a pivotal molecule involved in the pathogenensis of a wide variety of acute and chronic inflammatory disease states including many skin diseases such as psoriasis, graft-versus-host-disease (GVHD), contact dermatitis and leprosy reactions.
Pentoxifylline affects almost all factors responsible for blood viscosity (Table 1) and is indeed the first known hemorheologically active drug . The primary hemorheological effects of PTX are caused by increased red blood cell deformability and decreased blood viscosity. The mechanism by which this is achieved has been shown to involve increased erythrocyte adenosine triphosphate (ATP) and other cyclic nucleotide levels .
Hemorheological properties of PTX are not completely confined to its effects on red blood cells; by increasing intracellular cAMP levels, PTX leads to the inhibition of thromboxane synthesis and an increase of prostacyclin synthesis. Therefore, platelet aggregation and adhesion to vessel walls is also inhibited. In addition, it increases tissue plasminogen activator and plasmin and this complex of effects makes PTX a valuable drug for improving hypercoagulable states. Interestingly, PTX causes platelet disaggregation only in conditions in which the platelets are hyperaggregable, but does not cause prolonged bleeding or any platelet abnormalities in normal persons [4, 6].
Furthermore, PTX increases leucocyte deformability and regarding this new concept that polymorphonuclear leukocytes may play even a greater role in whole blood viscosity [7, 8], it can be considered as an almost complete rheologic drug.
Pentoxifylline increases fibroblast collagenases and decreases collagen, fibronectin and glycosaminoglycan production . Although, these effects could be due to anti TNF-α properties of PTX, studies have revealed that this inhibitory activities of PTX on fibroblasts are mediated by a separate mechanism .
Pentoxifylline is a non-selective inhibitor of cyclic-3', 5'-phosphodiesterase (PDE), which leads to a broad-spectrum effects against cell proliferation and inflammation.
Pentoxifylline is an inhibitor of production of IL-1 and IL-6, an inhibitor of T and B cell activation, and a suppressor of neutrophil degranulation. Furthermore, it has been shown that it reduces the expression of adhesion molecules such as ICAM-1, on keratinocytes and E-selectin expression on endothelial cells .
Pharmacokinetics, Dosage and Side Effects
Pentoxifylline is readily absorbed from the gastrointestinal tract and its peak plasma level is achieved within 2 hours, but it undergoes first-pass hepatic metabolism [12, 13, 14]. The usual adult dosage of PTX is 400 mg TID with meals. However, in patients with renal insufficiency the dose has to be adjusted.
Overall, PTX is a very safe drug and is usually well tolerated. Its most common side effects are those of the gastrointestinal tract and central nervous system which appear in approximately 3 percent of patients . The main central nervous system side effects are dizziness, headache, anxiety, and confusion. These side effects are dose-related and can be minimized by reduction of the dose.
Clinical applications in Dermatology
Peripheral vascular diseases
Several studies have shown that PTX therapy produces subjective and objective improvements in a significant percentage of patients with peripheral vascular disease and also improves walking distance by 18-59 percent in these patients [15, 16]. Indeed the main indication of PTX is for the treatment of intermittent claudication; it has been marketed in Europe since 1972 for this purpose.
Venous leg ulcers
Recent histological and immunocytochemical analyses of venous leg ulcers suggest that inflammatory reactions play a great role in these ulcers. These inflammatory reactions lead to fibrosclerotic remodeling of the skin and then to ulceration. The leukocyte activation is accompanied by the expression of integrins and by synthesis and release of many inflammatory molecules, including proteolytic enzymes, leukotrienes, prostaglandin, bradykinin, free oxygen radicals, cytokines, and possibly other classes of inflammatory mediators . As leukocytes become activated, they become rigid and immobile; this leads to further occlusion of small vessels and trophic changes in the overlying skin . With this in mind, the attention of many investigators has been drawn to use PTX as an adjunctive therapy in venous leg ulcers. Results of a prospective randomized, controlled study on 80 eligible patients with confirmed venous ulcers have shown complete healing in 57.5 percent of patients receiving PTX in comparison with 27.5 percent of patients in the control group (p=0.013). This study has concluded that PTX is an efficacious medication in the treatment of venous ulcers in patients unable to tolerate compression therapy . A systematic review has also shown that PTX with compression is more effective than placebo with compression in patients with venous leg ulcers .
Vasculopathies and vasculitides
Due to its multiple effects on various blood cell types and probably through its anti-inflammatory effects, PTX could be a useful drug in treating vasculopathies. Indeed, several studies have shown the beneficial effects of PTX in idiopathic livedoid vasculopathies and some authors suggest it as a drug of choice for this condition [20, 21, 22].
Cutaneous vasculitides are usually managed primarily with colchicine, dapsone, and prednisone. Theoretically, PTX can act as a sparing agent in different kinds of vasculitides, both through its extensive hemorheologic effects and also by neutralizing proinflammatory cytokines. Specifically, it seems that PTX works synergistically with dapsone in treating hypocomplementemic urticarial vasculitis [23, 24].
Pigmented purpuric eruptions
Although there is limited evidence, one study of three cases of Schamberg's disease revealed showed successful treatment with PTX. The authors suggested that PTX acts through its effects on adhesion molecules in this disease .
Perhaps the prototype of TNF-α mediated diseases in dermatology is psoriasis. Indeed, some of the new biologic drugs for psoriasis act by inhibition of this cytokine. The beneficial effects of PTX in psoriasis have been shown in nude mice in both in vivo and in vitro studies , but there is a lack of sufficient studies in humans.
Pentoxifylline can be used also as an adjuvant therapy in psoriasis. In at least two situations, its beneficial effects in psoriasis have been reported; it has been suggested that PTX counteracts many of the unwanted effects of cyclosporine on red blood cells, platelets and coagulation factors [4, 26]. One study has shown that PTX ameliorates cyclosporine nephrotoxicity in humans . In addition, abnormal metabolism of triglyceride is not an uncommon finding in psoriatic patients [28, 29] and may be also exaggerated after cyclosporine therapy . Because a possible beneficial of PTX is in reducing serum triglycerides, it seems that a combination of PTX and cyclosporine is a very sensible choice. Randomized, clinical trials are needed to compare both the clinical response and lipid profiles in psoriatic patients on cyclosporine with or without adjuvant PTX.
Furthermore, there is also some evidence that concomitant PTX therapy may reduce the incidence and severity of gastrointestinal complaints and flushing in patients receiving fumaric acid esters , a widely used anti-psoriatic drug in northern Europe.
An increase in TNF-α has been implicated in type II leprosy reaction.
In a study, serum TNF-α was assayed before and during treatment with PTX in 15 patients with erythema nodosum leprosum (ENL). The increased TNF-α levels recorded in the circulation during the reaction were dramatically reduced within three to seven days of the initiation of therapy. In vitro TNF-α production was assayed upon mononuclear cell culture stimulation with Mycobacterium leprae. A reduction of inducible TNF-α in peripheral blood mononuclear cells was seen after one to two weeks of in vivo administration of PTX. These data suggest that PTX inhibits TNF-α production in ENL patients both in vivo and in vitro; thus it may be useful in the treatment of this type of leprosy reaction .
Tumor Necrosis Factor-α has been also implicated in the immunopathogenesis of cutaneous leishmaniasis. It is expressed in lesions of patients with American cutaneous leishmaniasis and has been shown to be elevated in the serum of patients with mucocutaneous leishmaniasis .
Also, a very recent study has shown that PTX can prevent renal functional alterations induced by meglumine antimonate in rats . Therefore, it seems that PTX is an ideal adjuvant in treating patients with leishmaniasis.
Although a specific inciting antigen has not yet been identified for sarcoidosis, it appears to be a Th1-mediated disease; TNF-α likely plays a critical role in granuloma formation in this disease .
Pentoxifylline can almost completely inhibit spontaneous TNF-α production from alveolar macrophages of sarcoidosis patients . Clinically, in an open-label trial, Zabel et al. have documented that PTX is an effective drug in the treatment of pulmonary sarcoidosis , but specific studies addressing the treatment of cutaneous sarcoidosis have yet to be done.
Aphthosis and Behcet disease
There are some reports that have shown the efficacy of PTX in treating recurrent oral and genital aphthosis [42, 43, 44]. Furthermore, PTX has been used by many rheumatologists for the treatment of Behcet disease (BD). PTX reduces the severity and duration of the symptoms [45, 46]. Although these beneficial effects may be due to the anti-TNF-α properties of PTX, a recent study has shown that erythrocyte deformability is decreased in active BD patients in comparison with healthy control subjects. Hence, the therapeutic mechanism underlying the beneficial effect of PTX in BD is possibly the correction of impaired erythrocyte deformability . PTX can be also regarded as a preventive modality for thrombotic events, which are among the other characteristics of BD.
Increased levels of TNF-α have been demonstrated in many patients with AIDS ; Pentoxifylline has been shown to decrease TNF-α expression, serum fasting triglycerides, and HIV replication in these patients . Also, it has been documented that PTX is a safe and efficacious treatment for the pruritic papular eruption of HIV/AIDS, a common and usually recalcitrant manifestation of HIV infection .
Graft-versus-host disease (GVHD)
Cytotoxic T-lymphocyte -mediated tissue injury and inflammatory cytokines including TNF-α play important roles in the pathogenesis of GVHD. Therefore, theoretically PTX could be a useful drug in reducing the incidence of this disease. However, the existent studies concerning the prophylactic efficacy of PTX in GVHD are quite conflicting .
Miscellaneous (Kasabach-Merritt syndrome, pretibial myxedema, burn and radiation fibrosis)
One child achieved a significant increase in platelet count with PTX, which was utilized with good results between age 15 months to 5 years of age .
Theoretically, through its antifibfinolytic activities, PTX could be useful in treating fibroblast-mediated diseases such as pretibial myxedema. Pineda et al. have demonstrated that 2 months of therapy with PTX in combination with topical glucocorticoids resulted in reduction of thickness of skin lesions in a 48-year-old woman with pretibial myxedema; after 4 months, complete resolution of the lesions was observed. Interestingly her ophthalmopathy was also improved . Engin and his colleagues have reported another case of pretibial myxedema which was succesfully treated with a combination of PTX and intralesional triamcinolone acetonide .
A recent study suggests that Pentoxifylline has a direct effect on inhibiting burn scar fibroblasts. Perhaps, PTX will be a valuable drug for reducing burn scar contractures in the future .
The treatment of 34 radiation-induced superficial fibrotic lesions with pentoxifylline and vitamin E for 3 months revealed a significant effect of the Pentoxifylline-vitamin E combination in improving radiation-induced fibrosis .
In conclusion, it seems that PTX is able to help dermatologists in a wide spectrum of skin diseases (Table 2). However, the paucity of the clinical trials makes it difficult to draw definite conclusions about the degree of benefit of PTX in various clinical settings.
When using PTX therapy it should be kept in mind that in most cutaneous diseases the beneficial effects may not be evident until after several weeks or even months of treatment. For some diseases the full improvement may take several years. Some reports of treatment failure may be due to an inadequate therapy duration [57, 58].
Furthermore, it should be stressed that in most conditions PTX should be regarded as a valuable therapeutic adjuvant rather than a primary treatment. Specifically, PTX may best serve as a corticosteroid-sparing agent in skin diseases.
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