Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…In the next study, the peptide concentration in the small intestine of LDL receptor null (LDLR Ϫ / Ϫ ) mice on a Western diet (WD) predicted effi cacy as measured by the ability of the peptide to reduce tissue and plasma levels of proinfl ammatory oxidized metabolites of arachidonic and linoleic acids and by plasma SAA levels, but the plasma peptide levels again did not predict effi cacy ( 7 ). In these mouse studies ( 6,7 ), the dose required for effi cacy was far above the highest dose tested in the human clinical trials that did not demonstrate effi cacy ( 5 ). Additionally, we noted that the effective dose of these peptides tested in rabbits as measured by improvement in HDL anti-infl ammatory properties, plasma SAA levels, and aortic atherosclerosis was also higher than the doses used in the third study ( 8 ).…”

“…There were two reasons that a low dose of peptide was chosen for the clinical trials described in the third report, which did not demonstrate effi cacy ( 5 ). First, because of the need to chemically synthesize the 4F peptides, the cost of production was very high.…”

D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice

“…However, doses of 0.43 and 1.43 mg/kg did not alter HDL-anti-infl ammatory properties ( 10 ). Watson et al ( 11 ) targeted plasma levels of peptide. By administering a dose of 0.43 mg/kg by intravenous infusion, Watson et al ( 11 ) achieved plasma levels of ‫ف‬ 3,000 ng/ml and by SQ administration achieved plasma levels of ‫ف‬ 400 ng/ml of 4F peptide.…”

High-Density Lipoprotein

“…Because the plasma and liver concentrations of peptide after administering the peptide orally were 100-to 1000-fold lesser compared with administering the peptide subcutaneously, these data strongly suggest that the reduction of oxidized metabolites of arachidonic acid in the small intestine by the peptide led to the reduction in liver levels. 107 These results likely explain the failure of the clinical trial by Watson et al 105 The dose administered was likely too low to achieve the needed peptide levels in the small intestine. The results also suggest that a dose of peptide on the order of 40 to 100 mg/kg per day will be required for efficacy.…”

“…High plasma levels were achieved (≈3250 ng/mL), but there was no improvement in the HDL inflammatory index. 105 To understand these perplexing results, mice studies were performed. Surprisingly, when equal doses of peptide were administered, peptide levels were similar in the tissue of the small intestine, whether the peptide was administered orally or subcutaneously, but this was not the case in plasma or in liver where the plasma and liver levels, respectively, were 100-and 1000-fold higher after administering the peptide subcutaneously compared with orally.…”