Abstract 14009: Longitudinal Analysis Supports Reproducibility Of Treatment With Sildenafil In The Semaxanib/Hypoxia Rat Model Of Pulmonary Arterial Hypertension

Abstract

Rats develop translatable pulmonary arterial hypertension (PAH) after exposure to the VEGF antagonist semaxanib (SU5416) concurrent with hypoxia. Sildenafil is used clinically for PAH and as a positive control in this preclinical model. A longitudinal analysis was constructed by pooling data from discrete rat PAH studies conducted over an 8-year period to evaluate the stability and reproducibility of the SU5416/Hypoxia rodent model as well as the response to sildenafil. Sprague-Dawley rats were administered SU5416 on Day 1 and subsequently maintained in a low oxygen environment for 28 days. Sildenafil was given as a positive control in either prevention or treatment mode. Pulmonary hemodynamics were obtained on the final day as appropriate by design; hearts were also assessed for right ventricular hypertrophy. Prevention studies (≥17) were terminated following 28 days of hypoxia while most treatment studies (≥17) had a protocol-defined period of normoxia following hypoxia. In prevention studies, the mean of both systolic pulmonary arterial pressure (sPAP) and the right ventricular hypertrophy Fulton’s Index (FI) remained consistent across studies over the 7-year period: sPAP: PAH vehicle control (PAH-VC) 70 ± 19 mmHg (n = 190), sildenafil 51 ± 15 mmHg (n = 165), p<.05; FI: PAH-VC 0.5573 ± 0.1048 (n = 210), sildenafil 0.4984 ± 0.1007 (n = 172), p<.05. Sildenafil elicited mean reductions in sPAP of 28% and FI of 11% over the 7-year period. Mean survival rate was comparable for PAH-VC (96%) and sildenafil groups (99%).In treatment studies, the mean of both sPAP and FI remained consistent across studies over the 8-year period: sPAP: PAH-VC 89 ± 24 mmHg (n = 148) vs. sildenafil 67 ± 22 mmHg (n = 168), p<.05 vs PAH-VC; FI: PAH-VC 0.5938 ± 0.0944 (n = 168) vs. sildenafil 0.5336 ± 0.1077 (n = 173), p<.05 vs PAH-VC. Sildenafil elicited mean reductions in sPAP of 25% and FI of 10% over the 8-year period. Mean survival rate was comparable for PAH-VC (91%) and sildenafil groups (95%).The effects of sildenafil on reduction of PAH were stable and of similar magnitude in both prevention and treatment studies over an 8-year period. Thus, this longitudinal analysis indicates a reproducible and consistent effect of both the SU5416/Hypoxia PAH model and the use of sildenafil as a positive control.

An active peptide from yak inhibits hypoxia-induced lung injury via suppressing VEGF/MAPK/inflammatory signaling

“…In this study, we used them as positive controls. Comparing with other anti-hypoxia drugs, such as dexamethasone and sildenafi, salidroside is considered to have lower toxic side effects and better tolerability [ 40 , 41 ]. Unfortunately, this study did not directly compare the difference in peptide LV efficacy with dexamethasone or sildenafi, but other researchers have found that salidroside is as effective as dexamethasone or sildenafil [ 40 , 41 ].…”

“…Comparing with other anti-hypoxia drugs, such as dexamethasone and sildenafi, salidroside is considered to have lower toxic side effects and better tolerability [ 40 , 41 ]. Unfortunately, this study did not directly compare the difference in peptide LV efficacy with dexamethasone or sildenafi, but other researchers have found that salidroside is as effective as dexamethasone or sildenafil [ 40 , 41 ]. It suggests peptide LV may have resemble anti-hypoxia effect of dexamethasone or sildenafil, but putting them as direct control and additional studies in clinical trials is needed if peptide LV needs to further develop adjunct drug or functional food.…”

Tandem Vinylogous Aldol and Intramolecular [2 + 2] Cycloaddition toward Benzocyclobutenes by UV Light Photocatalysis

“…Different from reported approaches for BCB synthesis, this reaction proceeds smoothly at room temperature. To the best of our knowledge, this approach is the first case of the construction of BCBs via the light-catalyzed tandem reaction of 2-alkyl aromatic ketones and carbonyl compounds, and isatin is a widely employed building block for the synthesis of a wide variety of biologically active compounds, including clinically successful drugs, such as sunitinib, 34 semaxanib, 35 and toceranib. 36 We are convinced that this strategy not only showed a mild, clean, and economical method for the construction of BCBs but also presented application prospects in organic chemistry, such as the construction of organic compounds with complex structures.…”