A Novel, Easy-to-Use Staple Line Reinforcement for Surgical Staplers.

BACKGROUND: Staple line reinforcement (SLR) is a popular tool used by surgeons to increase staple line strength and improve peri-operative hemostasis. However, currently marketed buttress materials require special attention in attachment to the staple anvil and cartridge and may come loose during typical maneuvering of stapling procedures. We have evaluated a new SLR that has an attachment material that affixes buttress across the entire anvil and cartridge face to prevent slipping, twisting, sliding and/or bunching. METHODS: In benchtop and preclinical testing, the new buttress material (ECHELON ENDOPATH™ Staple Line Reinforcement) was compared to a commercially available SLR for physical characteristics, including strength, absorption, security on the anvil and cartridge during stapler manipulation, impact on the tissue healing response and tissue abrasion. The two SLR's were also compared to a staple line without buttress for hemostasis. RESULTS: The new SLR was 180% stronger initially and maintained a greater strength for up to 14 days of exposure to an in vitro solution (p≤0.001), even though it was lighter and exhibited a faster rate of degradation. The new buttress material maintained complete adherence to the anvil and cartridge throughout tissue manipulation, whereas the commercial product lost substantial coverage in 72% of samples. Both SLR's provided superior hemostasis to the non-buttress control, with minimal impact on tissue healing or abrasion. CONCLUSION: Because the new buttress material comes with attachment material affixed across the entire anvil and cartridge face of the stapler and maintains coverage during manipulations, it should be much easier to use. The physical characteristics of the new SLR were as good as or better than current product that requires the buttress to be applied to the cartridge and anvil. In addition, the new SLR is similar in hemostasis to standard products and superior to stapling without the use of buttress. Further research is needed to determine whether these preclinical benefits carry over into a clinical setting.

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Investigation of novel fumagillin analogues as angiogenesis inhibitors.

Modification of fumagillin was conducted to develop MetAP-2 inhibitors with desirable pharmacological properties. Replacement of the C4 side chain by benzyloxime preserves the inhibitory activity against MetAP-2 enzyme. Fumagillin analogues containing the C4 benzyloxime moiety were found to be very sensitive to the nature of the C6 substituent on the inhibition activity of HUVEC proliferation. This lack of correlation between MetAP-2 and HUVEC activities might be due to the cellular metabolism of the compounds by epoxide hydrolase, which is present in the cell. Compound (E)-3d, containing ethylpiperazinyl carbamate at C6 position, exhibited antiangiogenic effects similar to TNP-470 on matrigel plug assay and rat corneal micropocket assay.