Chronic Cancer-Related Pain: Continuous Perineural Infusion of Local Anesthetics as Alternative to Systemic Analgesic Drugs

Pain is a major concern for patients suffering from cancer. Although opioid drugs remain the gold standard for treatment of pain, little is known about the interest of continuous analgesia techniques as alternative. The aim of the present article is to detail the feasibility and to present the diversity of continuous perineural infusion of local anesthetic. A series of five patients suffering from different cancer-related pain is presented. A continuous perineural block was proposed to patients presenting with unbearable pain in an area innervated by a plexus or a nerve despite parenteral analgesic pharmacotherapy. All blocks were performed in a surgical theatre under sterile conditions. An initial bolus dose with 3.75 mg/mL ropivacaine was injected followed by a continuous infusion of 2 mg/mL of ropivacaine. Patient-controlled perineural analgesia was started at home by a nursing network. The technique, the efficacy, and the side effects were reported. Complete pain relief was noted 15 minutes after local anesthetic injection in the five cases, and efficacy was maintained during the following days at home, with no other analgesic treatment required. One patient restarted working a few weeks after catheter insertion. The catheter duration lasted for 12 to 110 days. One catheter was removed because of local anesthetic leak at the puncture point. Some paresthesia was noted in one patient. No other side effect was noted. No infection was reported. In selected patients, continuous perineural infusion of local anesthetics appears to be an attractive alternative to parenteral opioids for cancer-related pain. Further investigation is warranted to better define the place of these techniques in the armamentarium of cancer-related pain treatment.     

PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction,increased apoptosis and impaired neovascularisation

Prostate cancer is the leading cancer in North American men. Current pharmacological treatments are limited to anti-androgen strategies and the development of new therapeutic approaches remains a challenge. As a fundamentally new approach, we propose the inhibition of PACE4, a member of the proprotein convertases family of enzymes, as a therapeutic target in prostate cancer. We developed an inhibitor named the Multi-Leu peptide, with potent in vitro anti-proliferative effects. However, the Multi-Leu peptide has not been tested under in vivo conditions and its potency under such conditions is most likely limited, due to the labile characteristics of peptides in general. Using a peptidomimetic approach, we modified the initial scaffold, generating the analog Ac-[DLeu]LLLRVK-Amba, which demonstrates increased inhibitory potency and stability. The systemic administration of this peptidomimetic significantly inhibits tumor progression in the LNCaP xenograft model of prostate cancer by inducing tumor cell quiescence, increased apoptosis and neovascularization impairment. Pharmacokinetic and biodistribution profiles of this inhibitor confirm adequate tumor delivery properties of the compound. We conclude that PACE4 peptidomimetic inhibitors could result in stable and potent drugs for a novel therapeutic strategy for prostate cancer.     

Schulungsmaterial zur Minimierung von Arzneimittelrisiken

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Schulungsmaterial für Heilberufler und Patienten stellt eine wichtige Hilfe bei der sicheren Anwendung bestimmter...     

Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation

Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-α from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance.