Clinical studies of pentoxifylline
The anti-inflammatory properties of pentoxifylline have been confirmed in a range of clinical studies in diverse organ failure syndromes. In severe renal disease patients exhibit resistance to erythropoietin through a pro-inflammatory state characterised by increased TNFα, IFNγ and IL6. pentoxifylline improves erythropoietin sensitivity in these patients and this action is associated with reductions in serum TNFα and IFNγ [13]. In diabetic nephropathy pentoxifylline reduces proteinuria through inhibition of intraglomerular inflammatory signals. Clinical studies have demonstrated pentoxifylline as effective in reducing lung damage in the context of radiation damage, and cardiopulmonary bypass [13,14]. Ustunsoy et al (2003) for example found that pentoxifylline reduced levels of TNFα and IL6 when given at the time of bypass [14].
One of the largest scale clinical trials of pentoxifylline anti-inflammatory effects within the last decade, was the STOPAH trial [15]. Examining potential benefit in acute alcoholic hepatitis, no survival benefit was demonstrated, however no safety issues were reported in an inherently vulnerable, immunocompromised patient cohort. pentoxifylline preferential inhibition of macrophage function in alveoli, as opposed to hepatocytes, potentially explains this outcome [16].
Rainsford (2006) reviewed possible treatments for the lung complications associated with inflammatory cytokines in H5N1 “bird flu” and suggested that pentoxifylline should be considered for clinical trials in view of its pharmacology and safety profile [17]. These arguments appear equally suited to the case of COVID-19. Although we cannot describe the SARS-CoV-2 pulmonary syndrome as identical to that seen in H5N1, there are certainly parallels.
TNF has a pivotal role in orchestrating the production of a pro-inflammatory cytokine cascade. TNFα is thus considered to be a ‘master regulator’ of pro-inflammatory cytokine production [18]. Post mortem lung biopsies in COVID-19 showed interstitial oedema which would normally be the result of TNF induced increased capillary permeability [19,20]. This non cardiogenic pulmonary oedema (both interstitial and intra-alveolar) is often the first stage of COVID-19 acute lung injury that progresses through the cytokine storm to ARDS [20]. The recent description of thrombosis and endothelialitis in COVID-19 [20] raises the possibility that the rheological actions of pentoxifylline could have benefit in maintaining microvascular function.
Pentoxifylline has over 50 years safety record data of use in humans and has an extensive evidence base for tolerability and safety. Nevertheless, its safety in the context of COVID-19 has not been established and this would need close monitoring in a clinical trial setting. It is available in oral form with good bioavailability, and also can be delivered by intravenous injection. The usual dose orally is 1.2g daily in 3 divided doses. An inhalational formulation has been developed, originally for use in neonates. In COVID-19 the cytokine storm appears to be strongly centred in lung tissue, and accordingly inhaled pentoxifylline could be an optimum method for delivery at the highest concentrations where it is most effective, with minimal systemic exposure.
Use of a repurposed drug for COVID-19 may have multiple advantages in addition to its safety and tolerability experience. It is widely available as a generic agent, with multiple sources of supply and therefore manageable cost. There should be no patent protection issues in redirecting the agent to trials in COVID-19. This should be of acute interest as limited-resource areas begin to amass cases of COVID-19.