Postoperative Opioid Requirements Following Roux-en-Y Gastric Bypass in Patients Receiving Continuous Bupivacaine Through a Pump System: A Retrospective Review.

BACKGROUND: Patients who undergo Roux-en-Y gastric bypass (RYGB) surgery have self-reported considerable postoperative pain, often requiring opioid administration. OBJECTIVE: To determine whether continuous delivery of local anesthetic via an infusion pump system decreased postoperative opioid usage in post-RYGB patients. METHODS: The electronic health record was used to identify and review 289 patients who underwent RYGB at our institution from January 2009 to October 2011. The treatment group received a continuous infusion of 0.375% bupivacaine administered by intraperitoneal soaker catheter for 48 hours via an infusion pump; the control group did not receive a pump or local anesthetic. Both groups received general anesthesia, nausea prophylaxis, and pain medication. Pain management consisted of opioid-containing patient-controlled analgesia (PCA) for the first 24 hours. Patients transitioned to supplemental intravenous opioid boluses, plus an oral opioid, for the remainder of their stay. Opioid use was measured in terms of morphine equivalents. Secondary outcomes included visual analog scale (VAS) pain scores and length of hospitalization. RESULTS: Morphine equivalents over the postoperative time period studied were significantly lower in the bupivacaine group than the control group (133 vs 106 mg, respectively; P = .001). There was no significant difference in VAS scores between the 2 groups (P = .80). Finally, the length of hospitalization between the 2 groups did not differ (P = .77). CONCLUSIONS: We have shown that continuous infusion of bupivacaine, administered via a pain pump system, may have decreased postoperative opioid utilization. There were no differences in VAS scores or length of hospitalization between groups.

Solid-phase synthesis of prenylcysteine analogs.

Prenylcysteine derivatives are of interest for a variety of different biological reasons, including probing the CaaX protein processing pathway. A solid-phase synthesis protocol for the preparation of prenylcysteines using 2-chlorotrityl chloride resin as a solid support has been developed. A series of novel amide-modified farnesylcysteine analogs were synthesized in both high purity and yield under mild conditions. The farnesylcysteine analogs were evaluated using human isoprenylcysteine carboxyl methyltransferase as a biological target, and several new inhibitors, one with significantly enhanced potency, were identified.

Amide-substituted farnesylcysteine analogs as inhibitors of human isoprenylcysteine carboxyl methyltransferase.

N-Acetyl-S-farnesyl-L-cysteine (AFC) is the minimal substrate for the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). A series of amide-modified farnesylcysteine analogs were synthesized and screened against human Icmt. From a 23-membered library of compounds, six inhibitors were identified and evaluated further. The adamantyl derivative 7c was the most potent inhibitor with an IC(50) of 12.4 microM.

Synthesis of desthio prenylcysteine analogs: sulfur is important for biological activity.

N-Acetyl-S-farnesyl cysteine (AFC) is the minimal synthetic substrate for the enzyme Icmt, which methylates prenylated proteins. The desthio-AFC isostere 2 has been synthesized in racemic form. This analog was not an Icmt substrate, but instead a weak inhibitor with an IC50 of approximately 325 microM.

Computational and conformational evaluation of FTase alternative substrates: insight into a novel enzyme binding pocket.

Protein farnesyltransferase (FTase) is an important anticancer drug target. In an effort to develop isoprenoid diphosphate-based FTase inhibitors, striking variations have been observed in the ability of conservatively modified analogues to bind to the enzyme. For example, 2Z-GGPP is an alternative substrate with high binding affinity, while GGPP is not an alternative substrate. Using the availability of high-resolution FTase crystal structures, we have used pharmacophore and docking studies to elucidate a new binding pocket for isoprenoid analogues. The unique conformations between the first two isoprene units of 2Z-GGPP, but not GGPP, allows 2Z-GGPP to exploit this new binding pocket. The discovered conformation allows the molecule to adopt a reactive conformation while placing hydrophobic groups within the predominately hydrophobic binding pocket. This computational finding is supported by NMR studies on (13)C-labeled 2Z-farnesol, which confirm that the computationally predicted conformation is also favored in solution. These discoveries suggest that ligand conformational flexibility may be an important design consideration for the development of both inhibitors and alternative substrates of FTase.

The isoprenoid substrate specificity of isoprenylcysteine carboxylmethyltransferase: development of novel inhibitors.

Isoprenylcysteine carboxylmethyltransferase (Icmt) is an integral membrane protein localized to the endoplasmic reticulum of eukaryotic cells that catalyzes the post-translational alpha-carboxylmethylesterification of CAAX motif proteins, including the oncoprotein Ras. Prior to methylation, these protein substrates all contain an isoprenylcysteine residue at the C terminus. In this study, we developed a variety of substrates and inhibitors of Icmt that vary in the isoprene moiety in order to gain information about the nature of the lipophilic substrate binding site. These isoprenoid-modified analogs of the minimal Icmt substrate N-acetyl-S-farnesyl-L-cysteine (AFC) were synthesized from newly and previously prepared farnesol analogs. Using both yeast and human Icmt enzymes, these compounds were found to vary widely in their ability to act as substrates, supporting the isoprenoid moiety as a key substrate recognition element for Icmt. Compound 3 is a competitive inhibitor of overexpressed yeast Icmt (K(I) = 17.1 +/- 1.7 microm). Compound 4 shows a mix of competitive and uncompetitive inhibition for both the yeast and the human Icmt proteins (yeast K(IC) = 35.4 +/- 3.4 microm, K(IU) = 614.4 +/- 148 microm; human K(IC) = 119.3 +/- 18.1 microm, K(IU) = 377.2 +/- 42.5 microm). These data further suggest that differences in substrate specificity exist between the human and yeast enzymes. Biological studies suggest that inhibition of Icmt results in Ras mislocalization and loss of cellular transformation ability, making Icmt an attractive and novel anticancer target. Further elaboration of the lead compounds synthesized and assayed here may lead to clinically useful higher potency inhibitors.