Table 3:
Positive Therapeutic Outcomes in Preclinical and Clinical AP Studies
| Type of AP Therapy | Study Population |
Injury or Disease Model | Outcome | Ref. |
|---|---|---|---|---|
| AP Administration | ||||
| PLAP | Mouse | LPS | PLAP administration improved sepsis survival, possibly by halting its’ development | (Bentala et al. 2002) |
| PLAP | Mouse | LPS | PLAP treatment improved survival and lowered NO levels in septic mice | (Verweij et al. 2004) |
| IAP | Mouse & pig | LPS | IAP administration attenuates LPS toxicity up to 80%, resulting in increased survival and inhibits differentiation of white blood cell and thrombocyte counts | (Beumer2003) |
| IAP | Mouse | Sepsis | IAP treatment reduced local and systemic inflammatory responses, as well as distant damage in the liver and lungs | (van Veen et al. 2005) |
| IAP | Sheep | Sepsis | Administration of IAP in fecal peritonitis-induced septic shock improved gas exchange, decreased blood IL-6 levels, and increased survival time | (Su et al. 2006) |
| IAP | Phase IIa clinical trial | Sepsis | Infusion of IAP in severe sepsis and septic shock patients inhibits the upregulation of renal iNOS, leading to reduction of NO metabolite production and attenuated tubular enzymuria, resulting in overall improved renal function | (Heemskerk et al. 2009) |
| IAP | Randomized, double-blind, placebo-controlled clinical study | Sepsis | IAP administration significantly improved renal function in septic patients | (Pickkers et al. 2009) |
| IAP | Rat | Inflammatory bowel disease | IAP treatment alleviates epithelial layer damage associated with DSS in rat intestines | (Tuin et al. 2009) |
| IAP | Open-label, first-in-patient exploratory trial | Ulcerative colitis | IAP administration was associated with short-term improvement in UC disease activity | (Lukas et al. 2010) |
| IAP | Rat | NEC | Supplemental IAP has a protective role in experimental NEC | (Whitehouse et al. 2010) |
| IAP | Mouse | Antibiotic treatment |
IAP supplementation increased growth of commensal bacteria leading to restored gut microbiota lost to antibiotic treatment | (Malo et al. 2010) |
| IAP | Mouse | Sepsis | IAP treatment enhanced survival and reduced organ damage in septic mice | (Ebrahimi et al. 2011) |
| IAP | Phase IIa prospective randomized, double-blind, placebo-controlled clinical trial | Sepsis and AKI | Overall, IAP treatment improves renal function in patients with severe sepsis or sepsis shock with AKI | (Pickkers et al. 2012) |
| IAP | Rat | Inflammatory bowel disease | Intrarectally administered IAP in models of rats colitis resulted in a lower colonic weight and tissue damage score; normalized expression of neutrophil markers and IL-1β; and counteracted bacterial translocation | (Martinez-Moya et al. 2012) |
| IAP | Mouse | Multiple Sclerosis | Pre-symptomatic treatment of EAE with IAP reduces neurological symptoms | (Huizinga et al. 2012) |
| IAP | Rat | NEC | IAP supplementation decreased histologic injury scores and barrier permeability in the ileum of rat pups with NEC | (Rentea et al. 2012) |
| IAP | Mouse | Metabolic syndrome |
IAP supplementation inhibited absorption of endotoxins and improved the lipid profile in mice, resulting in prevention or reversal of metabolic syndrome | (Kaliannan et al. 2013) |
| IAP | Rat | NEC | IAP treatment decreased iNOS and TNF-α expression, and decreased LPS translocation into the serum of infant rats | (Rentea et al. 2013) |
| IAP | Rat | NEC | IAP supplementation decreased intestinal injury and inflammation, including TNF-α, IL-6 and iNOS by LPS in preterm rat intestine | (Heinzerling et al. 2014) |
| IAP | Mouse | Antibiotic- associated infections |
Antibiotics+IAP oral supplementation resulted in weight maintenance, reduced clinical severity, reduced gut inflammation, and improved survival following infection | (Alam et al. 2014) |
| recAP | Rat | LPS | recAP treatment has renal protective effects from LPS-induced damage | (Peters et al. 2015) |
| recAP | Rat | Renal ischemia and reperfusion; LPS | recAP exerted a clear renal protective anti-inflammatory effect | (Peters et al. 2016a) |
| AP Inhibition | ||||
| Levamisole | Prospective clinical trial | Colon cancer | The addition of levamisole to 5FU-adjuvant therapy improved survival in stage II and III colon cancer patients | (Taal et al. 2001) |
| L-Phen | Rat | LPS | Suggest that lAPs in the gastrointestinal tract reduce LPS content in serum | (Koyama et al. 2002) |
| SBI-425 | Mouse | Medial vascular calcification | TNAP inhibition significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle-treated controls | (Sheen et al. 2015) |
| SBI-425 | Mouse | Hypophosphatasia | TNAP inhibition reduces calcium and lipid levels to improve the course of coronary atherosclerosis | (Romanelli et al. 2017) |
| SBI-425 | Mouse | Pseudoxanthoma elasticum (PXE) | TNAP inhibition attenuated calcification, altering disease development and progression in vivo | (Ziegler et al. 2017) |
PLAP: placental alkaline phosphatase; IAP: intestinal alkaline phosphatase; LPS: lipopolysaccharide; NO: nitric oxide; iNOS: inducible nitric oxide synthase; DSS: dextran sodium sulfate; NEC: Necrotizing enterocolitis; AKI: acute kidney injury; EAE: experimental autoimmune encephalomyelitis; recAP: human recombinant alkaline phosphatase; L-Phen: L-phenylalanine