Table 2.

Nonexhaustive list of therapeutics to reduce excessive neutrophil activity

Therapeutics	Principle	Level strength of evidence*	References
Topical
Lower extremity compression	↓ Edema and venous hypertension ↓ Protease levels in CVLU tissue	Level I	(43)
Negative pressure therapy	Removes exudates containing excessive proteases  and proinflammatory mediators	Level II	(81–83)
Mechanism-based dressings	To sequester, remove or inactivate excessive  proteases	Level I	(22,49,68,97–101)
Doxycycline	Inhibits MMP	Level II	(84–87,92,93)
Systemic
Pentoxifylline	Improves microcirculation of leg ↓ Neutrophil adhesion to endothelium ↓ Proinflammatory cytokine synthesis ↓ Free oxygen radical formation by neutrophils	Level I	(102–106)
MPFF	↓ Synthesis of prostaglandins, free oxygen radicals,  and inhibits leukocyte trapping and activation	Level I	(107–110)
EPA + DHA supplementation	↑ Endogenous production of lipid mediators that  reduce neutrophil influx ↓ Free oxygen radicals by leukocytes ↑ Macrophage clearance of apoptotic neutrophils	Level II	(26,112–117)

^*Level I: Meta-analysis of multiple randomized clinical trials (RCTs) or at least two RCTs support the intervention. Level II: Less than level I, but at least one RCT and at least two significant clinical series or expert opinion papers with literature reviews supporting the intervention. Experimental evidence convincing, but not yet supported by adequate human experience is included. Level III: Suggestive data of proof of principle, but lacking sufficient data such as meta-analysis, RCT, or multiple clinical series. MMP, matrix metalloproteinase; MPFF, micronized purified flavonoid fraction; EPA + DHA, eicosapentanoic acid and docosahexanoic acid—polyunsaturated fatty acids.