TABLE 1.
Selected New Candidate Drugs With a Proven Effect in Reducing PP in Preclinical Studies and in Some Clinical Studies
| Preclinical Studies | POC Studies | ||||||
|---|---|---|---|---|---|---|---|
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| Drugs | Purported Site of Action (Intrahepatic, Extrahepatic, or both) | Effect Other Than ↓ in PP | Potential Deleterious Signal | Reduced HVPG | Positive Effect Other Than on HVPG | AEs Observed | Phase 3 Trials |
|
| |||||||
| Statins | lntrahepatic(10,24,46) | Antifibrotic(47) | Rhabdomyolysis(24) | Yes(16,48,49) | Increased in ICG clearance(16) | Rhabdomyolysls, liver toxicity(17) | Yes (decrease mortality(17) |
| PDE5 inhibitors | lntrahepatic(50–52) | Antifibrotic(52) | — | ± (discordant)(53–57) | Erectile dysfunction | Hypotension | No |
| Sorafenib (anti-VEGF) | Both(58–60) | Antifibrotic, antiangiogenic(69) | Hepatic Injury(61) | ± (discordant)(62–64) | Improved MAP | Multiple | No |
| Poorly absorbed antibiotics (rifaximin, norfloxacin) | Extrahepatic(65) | Decreased bacterial translocation(65) | — | ± (discordant)(66–70) | Less HE, less decompensation(66,67) | — | No? |
| Caspase inhibitors | Both(71,72) | Liver injury, flbrosis(71) | — | Yes(73) | Decrease AST(74) | — | No |
| FXR agonists | Both(76–77) | Antifibrotic, decreased bacterial translocation(78–81) | — | Yes(82) | — | No | |
| Serelaxin | Intrahepatic(83) | Improved renal perfusion(84) | — | No data(84) | Improved renal perfusion(84) | — | No |
| Enoxaparin | Both(86,86) | Antifibrotic(85) | — | Ongoing trial (NCT02643212) | Decreased decompensation, less portal vein thrombosis(87) | — | |
| Endothelin-A receptor antagonists | lntrahepatic(88,89) | Antifibrotic(89) Antiangiogenic(90) |
— | ± (discordant)(91,92) | Decreased pulmonary arterial pressure (treatment of portopulmonary hypertension(91) | Decreased MAP(91) | No |
| Thalidomide | Intrahepatic(93,94) | Antifibrotic, antiangiogenic, reduced systemic inflammation(93,94) | — | Yes(95) | Reduced systemic inflammation(95) | — | — |
| Angiotensin II type 1 receptor blocker | lntrahepatic(96,98) | Antifibrotic,(98) improved renal perfusion as low dose(99) | Arterial hypotension(96) | ± (discordant)(100–106) | Antifibrotic(100) | Arterial hypotension, renal dysfunction(105,106) | No |
| Taurine | Intrahepatic and extrahepatic(107) | Antifibrotic(107) | — | Yes(108) | — | — | — |
Additional references (from #46 on) are provided as Supporting Information.
Abbreviations: AST, aspartate aminotransferase; FXR, farnesoid X receptor; MAP, mean arterial pressure; PDE5, phosphodiesterase-5; PP, portal pressure; VEGF, vascular endothelial growth factor.