Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain?

The unique pharmacology of remifentanil makes it a popular intra-operative analgesic. Short-acting opioids like remifentanil have been associated with acute opioid tolerance and/or opioid-induced hyperalgesia, two phenomena which have different mechanisms and are pharmacologically distinct. Clinical studies show heterogeneity of remifentanil infusion regimens, durations of infusion, maintenance of anaesthesia, cumulative dose of remifentanil and pain measures, which makes it difficult to draw conclusions about the incidence of acute tolerance or hyperalgesia. However, it appears that intra-operative remifentanil infusion rates of above 0.25 µg.kg-1 .min-1 are associated with higher postoperative opioid consumption, suggesting tolerance. Infusion rates greater than 0.2 µg.kg-1 .min-1 are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia. The use of concurrent multimodal analgesia, especially N-methyl-D-aspartate receptor antagonists, may be an effective preventive strategy. The clinical significance and long-term consequences of these entities is still uncertain.

D-Amino acid oxidase-induced oxidative stress, 3-bromopyruvate and citrate inhibit angiogenesis, exhibiting potent anticancer effects.

Angiogenesis is critical for cancer growth and metastasis. Steps of angiogenesis are energy consuming, while vascular endothelial cells are highly glycolytic. Glioblastoma multiforme (GBM) is a highly vascular tumor and this enhances its aggressiveness. D-amino acid oxidase (DAO) is a promising therapeutic protein that induces oxidative stress upon acting on its substrates. Oxidative stress-energy depletion (OSED) therapy was recently reported (El Sayed et al., Cancer Gene Ther, 19, 1-18, 2012). OSED combines DAO-induced oxidative stress with energy depletion caused by glycolytic inhibitors such as 3-bromopyruvate (3BP), a hexokinase II inhibitor that depleted ATP in cancer cells and induced production of hydrogen peroxide. 3BP disturbs the Warburg effect and antagonizes effects of lactate and pyruvate (El Sayed et al., J Bioenerg Biomembr, 44, 61-79, 2012). Citrate is a natural organic acid capable of inhibiting glycolysis by targeting phosphofructokinase. Here, we report that DAO, 3BP and citrate significantly inhibited angiogenesis, decreased the number of vascular branching points and shortened the length of vascular tubules. OSED delayed the growth of C6/DAO glioma cells. 3BP combined with citrate delayed the growth of C6 glioma cells and decreased significantly the number and size of C6 glioma colonies in soft agar. Human GBM cells (U373MG) were resistant to chemotherapy e.g. cisplatin and cytosine arabinoside, while 3BP was effective in decreasing the viability and disturbing the morphology of U373MG cells.

Comparison of long-term surgical success of Ahmed Valve implant versus trabeculectomy in open-angle glaucoma.

AIM: To compare the long-term intraocular pressure (IOP) outcomes of Ahmed Glaucoma Valve (AGV) implantation to trabeculectomy with mitomycin C (MMC) in open-angle glaucoma (OAG). METHODS: 78 OAG patients who underwent AGV implantation were matched with respect to age, preoperative surgery, preoperative IOP and preoperative medicines to 88 OAG patients who underwent trabeculectomy with MMC with a minimum of 3 years' follow-up. The cumulative probability of success between the two groups with different criteria was analysed: (1) an IOP < or =21 mm Hg and a reduction of IOP>/=15% from baseline; and (2) an IOP < or =18 mm Hg and a reduction of IOP > or =20% from baseline. No loss of light perception, no additional glaucoma surgery and no hypotony were also required. RESULTS: The 5-year cumulative probability of success was not statistically significant between eyes that had an AGV or trabeculectomy with MMC when success was defined as criteria A (p = 0.094). However, when success was defined according to criteria B, eyes undergoing trabeculectomy with MMC had a higher rate of success (p = 0.024). CONCLUSIONS: Trabeculectomy with MMC has a significantly higher 5-year cumulative probability of success compared with AGV implants when greater reduction IOP is necessary.