A wide range of medical therapies has been used for PD,^3–9 but there is no universally agreed upon standard medical treatment. Furthermore, medical treatment is generally thought to be efficacious only in the early phase of the disease, before plaque hardening and/or calcification has occurred.¹⁰ As such, the search for a pharmaceutical option that is effective, well tolerated, and effective in both the acute and chronic phase of PD continues.

Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor with anti-inflammatory properties that has been used to treat claudication.¹¹ PTX has also been used to decrease inflammation and fibrosis in kidney transplants, open heart surgery, dermatological conditions and after radiation injury.^12–16 PTX has also been shown to reduce renal calcification in a rat mode of cisplatin-induced kidney injury.¹⁷ With respect to penile diseases, case reports have suggested that PTX may prevent intracavernosal fibrosis after priapism¹⁸ and decrease calcification in new-onset PD.¹⁹ In general, the side effects of PTX are mild and consist of nausea, dizziness and headache.¹¹ These traits make PTX an interesting potential option for PD therapy.

A number of previous studies have reported declines in plaque size and consistency with medical therapies. Levine²⁰ reported a substantial reduction in plaque size in 38 men treated with biweekly penile verapamil injections over a 6-month period; substantial plaque softening was also noted in treated men. Rehman et al.⁸ reported similar results in a single-blind randomized study of 14 men treated with intralesional verapamil. In a larger randomized clinical trial of 117 men, Hellstrom et al.⁴ reported greater rates of plaque shrinkage and softening in men treated with intralesional injection of interferon alpha-2b. However, a smaller trial of 30 men with PD were treated with intralesional interferon weekly for 12 weeks versus vitamin E 400 IU daily, as a control group did not demonstrate any significant differences between groups or changes over time.⁵ Most recently, Jordan²¹ reported on 25 patients with PD who were treated with intralesional injection of clostridial collagenase (two cycles of three injections). Significant declines in mean plaque length and width were noted at 3-, 6- and 9-month follow-up time points. Although these trials suggest a number of different treatments, which may be efficacious in managing penile plaques, calcification was not the primary end point in any of these and it is therefore unclear whether or not these modalities are useful in calcified PD. Indeed, for several of these trials, tunical calcification was not explicitly assessed or was an exclusion criterion for enrollment.^4,8,21

It has been demonstrated in vitro that cells derived from both normal tunica albuginea and PD plaque express osteogenic markers and have the capacity to undergo calcification. Incubation with tumor growth factor-beta, a known mediator of the PD phenotype,²² was shown to induce differentiation of cells into osteoblasts and myofibroblasts. This finding suggests that differentiation of cells along the osteoblast lineage is one possible mechanism for penile calcification in clinical PD.²³

Although some data suggest that PTX blocks the tumor growth factor-beta pathways,²⁴ the mechanism by which PTX might induce regression of calcified plaques is unclear. PTX has been shown to improve microcirculation through reducing blood viscosity. PTX increases erythrocyte deformability, decreases platelet aggregation and decreases fibrinogen levels.^25,26 Furthermore, in an animal model, PTX was associated with increasing fibrinolytic activity in the peritoneum leading to a decrease in formation of peritoneal adhesions.²⁷ This may be relevant to PD as it has been shown that fibrin can induce PD-like lesions in animal models.²⁸ Therefore, along with its antifibrotic and anti-inflammatory properties, PTX may increase microcirculation in the site of fibrotic and calcified plaques, leading to faster plaque resolution and a decrease in calcification over time. Further study of mechanisms will be required to determine the actual activity of PTX in PD plaques.

Several limitations of this study are worth noting. Our relatively small sample size precluded a comprehensive multivariable analysis and the population was not randomized at baseline. Objective data on change in penile curvature, plaque volume, erectile function and erectile pain were not universally collected and therefore could not be included in the analysis. Because of this study design, it is possible that systematic differences between men taking PTX and those not taking PTX can explain some of the differences observed. It is also possible that men taking PTX were observed differentially relative to men not receiving PTX. Furthermore, unmeasured confounders could account for outcome differences between men who were or were not treated with PTX. As such, these results should be considered preliminary.