Effect of chronic lithium administration on endothelium-dependent relaxation of rat mesenteric bed: Role of nitric oxide

The mechanism of action of lithium, an effective treatment for bipolar disease, is still unknown. In this study, the mesenteric vascular beds of control rats and rats that were chronically treated with lithium were prepared by the McGregor method, and the mesenteric vascular bed vasorelaxation responses were examined. NADPH-diaphorase histochemistry was used to determine the activity of NOS (nitric oxide synthase) in mesenteric vascular beds. We demonstrated that ACh-induced vasorelaxation increased in the mesenteric vascular bed of rats treated with lithium. Acute No-nitro-L-arginine methyl ester (L-NAME) administration in the medium blocked ACh-induced vasorelaxation in the control group more effectively than in lithium-treated rats, while the vasorelaxant response to sodium nitroprusside, a NO donor, was not different between lithium-treated and control groups. Acute aminoguanidine administration blocked ACh-induced vasorelaxation of lithium-treated rats, but had no effect in the control rats. Furthermore, NOS activity, determined by NADPH-diaphorase staining, was significantly greater in the mesenteric vascular beds from chronic lithium-treated rats than in those from control rats. These data suggest that the enhanced ACh-induced endothelium-derived vasorelaxation in rat mesenteric bed from chronic lithium-treated rats might be associated with increased NOS activity, likely via iNOS. Simultaneous acute L-NAME and indomethacin administration suggests the possible upregulation of EDHF (endothelium-derived hyperpolarizing factor) in lithium-treated rats. © 2007 NRC

Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis

Background Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 - 250 mg. The aim of this review was to evaluate the safety of oral naltrexone by examining the risk of serious adverse events (SAEs) in randomised controlled trials (RCTs) of naltrexone compared to placebo. Methods A systematic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, other databases and clinical trials registries was undertaken up to March 2018. Parallel placebo-controlled RCTs longer than 4 weeks published after 1/1/2001, of oral naltrexone at any dose were selected. Any condition and age group were included, excluding only studies for opioid or ex-opioid users, due to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook throughout. Numerical data was independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane Risk of Bias Tool. Meta-analyses were performed using Stata 15 and R, using random and fixed effects models throughout. Results Eighty-nine RCTs with 11194 participants were found, studying alcohol use disorders, various psychiatric disorders, impulse control disorders, other addictions, obesity, Crohn’s disease, fibromyalgia and cancers. Twenty-six studies (4,960 participants) recorded SAEs occurring by arm of study. There was no evidence of increased risk of SAEs for naltrexone compared to placebo, relative risk (RR) 0.84 (95% CI: 0.66 to 1.06). Sensitivity analyses pooling risk differences supported this conclusion (RD = -0.01 (-0.02, 0.00)) and subgroup analyses showed that results were consistent across different doses and disease groups. The quality of evidence for this outcome was judged high using the GRADE criteria. Conclusions Naltrexone does not appear to increase the risk of SAEs over placebo. These findings confirm the safety of naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications

Scanning Probe Microscopy Study of Electronic Properties in Alkyl-substituted Oligothiopene-based Field-Effect Transitors

AbstractIt appeared in the past decades that semi-conducting organic liquid crystals could easily replace the inorganic semi-conductors to manufacture field-effect transistors (FET). They can be easily processed by simple methods such as inkjet printing. These simple and cheap manufacturing methods pave the way to new applications for plastic electronics: electronic tags, biosensors, flexible screens, … The performance of these liquid crystal nanomaterials is due to their specific nanoscale structure. However, one limitation to the improvement of organic electronic devices is an incomplete understanding of their optoelectronic properties at the nanoscale. The organic semiconductor films often contain a combination of many ordered and disordered regions, grain boundaries and localized traps. These features impact charge transport and trapping at the sub-100nm length scales [1]. Electrical SPM techniques such as STM, KPFM, EFM and CS-AFM have the potential to provide the correlation between the electronic properties directly and local film structure and have already made important contributions to the field of organic electronics. Here we report on the investigation of the structural and electronic properties of p-conductive organic field-effect transistors based on alkyl-substituted oligothiophenes with bottom-contact structure. For this purpose we use atomic force microscopy (AFM) and Kelvin-probe force microscopy (KPFM) in dual frequency mode under ambient conditions. This study helps to determine the local potential in the channel of active OFETs. On the other hand the molecular arrangements of these molecules on the HOPG surface have been studied using scanning tunnelling microscopy (STM) at the liquid-solid interface

Oligothiophene-Based Organic Thin-Film Transistors: A Kelvin Probe Force Microscopy Study of the Electronic Properties

ABSTRACTIn the past decades organic thin film transistors (OTFTs) have been notably studied due to their interesting properties. Not only they can be processed by simple methods such as inkjet printing but also open the doors to new applications for cheap plastic electronics including electronic tags, biosensors, flexible screens,… However, the measured field-effect mobility in OTFTs is relatively low compared to inorganic devices. Generally, such low field-effect mobility values result from extrinsic effects such as grain boundaries or imperfect interfaces with source and drain electrodes. It has been shown that reducing the number of grain boundaries between the source and drain electrodes improves the field effect mobility.1-3 Therefore, it is important to understand the transport mechanisms by studying the structure of organic thin films and local electrical properties within the channel and at the interfaces with source and drain electrodes in order to improve the field-effect mobility in OTFTs. Kelvin probe force microscopy (KPFM) is an ideal tool for that purpose since it allows to simultaneously investigation of the local structure and the electrical potential distribution in electronic devices. In this work, the structure and the electrical properties of OTFTs based on dioctylterthiophene (DOTT) were studied. The transistors were fabricated by spin-coating of DOTT on the transistor structures with treated (silanized) and untreated channel oxide. The potential profiles across the channel and at the metal-electrode interfaces were measured by KPFM. The effect of surface treatment on hysteresis effects was also studied. Smaller crystals and a lower threshold voltage were observed for the silanized devices. Hysteresis effects appeared to be less important in modified devices compared to the untreated ones.</jats:p

Pharmacological options for the management of refractory cancer pain—what is the evidence?

Refractory cancer pain that does not respond to standard opioid and/or co-analgesic therapy occurs in 10–20 % of patients. Risk factors include young age, neuropathic pain type, incident pain, psychological distress, previous opioid use, high tolerance, a history of addiction and impaired cognition. The management of patients with refractory pain remains a challenge. Treatment options include opioid manipulation (parenteral delivery, rotation, combination, methadone and buprenorphine), non-opioids and co-analgesics (paracetamol, non-steroidal anti-inflammatory agents, antidepressants and anticonvulsants), NMDA receptor antagonists, cannabinoids, lignocaine and corticosteroids. The evidence of benefit for any of these agents is weak, and each additional agent increases the risk of adverse events. Evidence-based guidelines cannot, therefore, be developed at present. New approaches are recommended including targeted opioid therapy, multimodal analgesia, a goal-oriented approach to pain management and increasing use of the multidisciplinary team and support services

Interventional options for the management of refractory cancer pain--what is the evidence?

PURPOSE: Pain is the most common symptom in cancer patients. Standard pain treatment according to the WHO three-step analgesic ladder provides effective pain management in approximately 70-90% of cancer patients. Refractory pain is defined as not responding to "standard" treatments. Interventional analgesic techniques can be used in an attempt to control refractory pain in patients in whom conventional analgesic strategies fail to provide effective pain relief or are intolerable due to severe adverse effects. This systematic review aims to provide the latest evidence on interventional refractory pain management in cancer patients. METHODS: Systematic literature search in Cochrane, EMBASE and PubMed including reviews and randomised controlled trials (RCTs) and non-randomised controlled trials in the absence of reviews. RESULTS: Neuraxial analgesia may play a role in refractory cancer pain management. Paravertebral blocks decrease the incidence of persistent post-surgical pain after breast cancer. Coeliac plexus blocks improve pain scores in refractory pancreatic cancer pain for up to 4 weeks after the intervention with fewer burdensome side effects as compared to opioids. Cordotomy has mainly been studied in mesothelioma, and the case series suggest possible benefit for pain at the expense of a relatively high risk of side effects. CONCLUSIONS: Overall, very few RCTs have been conducted on interventional pain techniques. In reality, it is very difficult to undertake large controlled trials for a number of reasons. Therefore, today's best evidence for practice may be from large case series of comparable patients with careful response and toxicity evaluation and follow-up

Therapeutic Challenges in Cancer Pain Management: A Systematic Review of Methadone

The proven therapeutic efficacy of methadone in cancer pain is hindered by a challenging pharmacokinetic-pharmacodynamic profile, considerable interpatient variation, and increasing concern about the complexities of dosing. The objective of this study was to assess the evidence for the use of methadone in cancer pain management. The authors conducted a systematic literature search for randomized controlled trials (RCTs) published post the 2007 Cochrane review of methadone in cancer pain. Trial quality was assessed using the Oxford Quality Scoring System and Cochrane Handbook for Systematic Reviews of Interventions. Of the 152 abstracts found, 4 were RCTs (272 participants). Two RCTs compared the efficacy and safety of methadone with placebo or active control and two investigated rotation to methadone from other opioids. The studies used different routes of administration, dosing, initiation, and titration of methadone and distinct pain scoring tools and did not address the issues raised by the Cochrane review. Methadone has an important role in the management of cancer pain, with many advantages including low cost, high oral bioavailability, rapid onset of action, once-daily dosing, and postulated benefits in difficult pain control scenarios. However, due to limited research in this area, methadone dosing remains a challenge, with vigilant dose initiation, adjustment, and monitoring required. There is a need for further studies using standardized methodology to evaluate the optimal dosing strategy of methadone, the effect on different types of pain, and the role of pharmacokinetics and pharmacogenomics in clinical outcomes.No Full Tex

Morphine and breast tumor metastasis: the role of matrix-degrading enzymes

Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co-cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment