Table 1.
Clinical perspective for the usage of soluble epoxide hydrolase inhibitors in human health
| Disease state | Clinical perspective |
|---|---|
| Inflammation | In many models, sEHIs compare favorably with COXIBs in reducing inflammation. However, the best results are obtained with cotreatment of sEHIs with inhibitors of the COX or LOX pathway. sEHIs also reduce some side effects of COXIBs. |
| Inflammatory pain | sEHIs reduce inflammatory pain, but penetrating this market will be difficult because numerous drugs already exist in this area. Reducing pain in the companion animal area, however, is an unmet need. sEHIs appear to provide better safety profiles than do existing treatments for the treatment of chronic inflammatory pain. |
| Neuropathic pain | Because neuropathic pain is an unmet medical need, the analgesic effects of sEHIs suggest high potential for therapeutic benefit. In addition, sEHIs have the potential to be used in synergistic combinations with COX and PDE inhibitors. |
| Hypertension | sEHIs reduce hypertension in numerous but not all animal models. In addition, they often are less effective than existing drugs. One sEHI failed in a Phase IIA human clinical trial for hypertension. However, sEHIs can help reduce the hypertensive side effects of other drugs, including NSAIDs and antiangiogenesis compounds. |
| Cardiac hypertrophy/arrhythmia | In animal models, sEHIs reduce cardiac hypertrophy, arrhythmia, and electrical remodeling. These results provide a strong scientific basis for targeting heart failure and cardiac arrhythmia in humans. |
| Atherosclerosis/aneurysm | In rodent models, sEHIs effectively reduce atherosclerotic lesions and attenuate abdominal aortic aneurysm formation. |
| Renal failure | sEHIs display a protective effect on kidney damage induced by various conditions, including hypertension, inflammation, and chemotherapeutics. |
| Blood clotting | EETs reduce platelet aggregation. sEHI cotreatment with COX2 inhibitors does not result in an imbalance in prostacyclin and thromboxane or an increase in 20-HETE. Thus, sEHIs could increase the safety of COX2-selective drugs. |
| Stroke/heart attack | In rodent and dog models, sEHIs reduce infarct size and ischemia-reperfusion injury resulting from stroke and heart attack. |
| COPD | In a smoke-induced rat COPD model, sEHIs reduce lung inflammation and improve lung function. This benefit might extend to other disorders involving pulmonary inflammation. |
| Pulmonary hypertension | In rodent models, sEHIs show promise in treating pulmonary hypertension. However, some EpFAs increase pulmonary vascular remodeling, pulmonary artery constriction, and hypertension. The hypoxia-driven pulmonary vasoconstriction could be used to increase blood oxygenation. |
| Diabetes/metabolic syndrome | sEHIs tend to normalize dysregulated glycemic states in many but not all models of diabetes and metabolic syndrome. Unexpectedly, sEHIs and EETs are efficient at modulating insulin secretion in both type 1 and type 2 diabetes through a range of mechanisms. sEHIs currently are more attractive in treating the comorbidities associated with diabetes than in treating the underlying disease. |
Abbreviations: 20-HETE, 20-hydroxyeicosatetraenoic acid; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; COXIB, COX2-selective inhibitor; EET, epoxyeicosatrienoic acid; EpFA, epoxy-fatty acid; LOX, lipoxygenase; NSAID, nonsteroidal anti-inflammatory drug; PDE, phosphodiesterase; sEH, soluble epoxide hydrolase; sEHI, soluble epoxide hydrolase inhibitor.