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- Transversus abdominis plane infiltration for laparoscopic gastric banding: A pilot study. [Journal Article]
- World J Gastrointest Surg 2014 Feb 27; 6(2):27-32.
To estimate an effect size for the transversus abdominis plane (TAP) infiltration on quality of recovery in patients undergoing laparoscopic gastric band surgery.The pilot study was a randomized, double blinded, placebo controlled trial. Patients undergoing laparoscopic gastric band surgery were randomized to receive a bilateral TAP infiltration with 20 mL of 0.5% ropivacaine or saline. The evaluated outcomes included quality of recovery-40 (QoR-40) at 24 h, postoperative opioid consumption and pain. Data was examined using the Mann-Whitney U test.Nineteen subjects were recruited. There was a positive trend favoring the TAP infiltration group in global QoR-40 scores at 24 h after surgery, median [interquartile range (IQR)] of 175.5 (170-189) compared to 170 (160-175) in the control group (P = 0.06). There also a positive trend toward a lower cumulative opioid consumption in the TAP infiltration group, median (IQR) of 7.5 (2.5-11.5) mg iv morphine equivalents compared to 13 (7-21.5) in the control group (P = 0.07). Correlation analysis (Spearman's Rho) demonstrated an inverse relationship between 24 h cumulative opioid consumption and global QoR-40 scores, -0.49 (P = 0.03).The use of multimodal analgesic techniques to reduce opioid related side effects is particularly desirable in morbidly obese patients undergoing gastric reduction surgery. The TAP infiltration seems to have a clinically important effect in reducing postoperative opioid consumption and improve quality of recovery after laparoscopic gastric band surgery in morbid obese patients. Future studies to confirm the beneficial effects of the TAP infiltration in these patients are warranted.
- Regulation of opioid drugs in thai government hospitals: Thailand national survey 2012. [Journal Article]
- Indian J Palliat Care 2014 Jan; 20(1):6-11.
Palliative care in Thailand was not well developed in the past. Previous studies showed that the actual prescription of opioids was underutilized in palliative care by physicians compared with the estimated opioid need of patients. However, there were no studies regarding the regulation of opioids in Thailand.To provide an up-to-date overview of the role of multidisciplinary teams in the regulation of opioids in Thai government hospitals.A questionnaire survey study was conducted from January to April 2012.The questionnaire was distributed to entire population of government hospitals in Thailand and all private hospitals in Bangkok. There were 975 hospitals, including 93 private hospitals in Bangkok and 882 government hospitals.Results are presented as a frequency and percentage.Special opioid prescription forms must be signed by doctors for all opioid prescriptions. Three-fourths of hospitals totally prohibited prescribing oral opioids by palliative care Advance Practice Nurses. Pharmacists were permitted to correct the technical errors on a prescription of oral morphine only after notifying the prescribing doctor in nearly 60% of hospitals. In terminal patients who could not go to the hospitals, caregivers were permitted to collect the opioids on behalf of patients in nearly 80% of hospitals.Our results illustrate that the regulation of opioids in government hospitals is mainly dependent on physician judgment. Patients can only receive oral morphine at a hospital pharmacy.
- Healthcare workers knowledge and attitude toward palliative care in an emerging tertiary centre in South-west Nigeria. [Journal Article]
- Indian J Palliat Care 2014 Jan; 20(1):1-5.
Palliative care is an emerging area of medicine with potential to affect positively many chronically ill patients. This study investigated the knowledge and attitude of healthcare workers in a tertiary level hospital in Nigeria where a palliative care unit is being established.The study was a cross-sectional questionnaire-based study carried out among healthcare workers in Ekiti State University Teaching Hospital, Ado-Ekiti, south-west Nigeria. The questionnaire had sections about definition of palliative care, its philosophy, communication issues, medications, and contexts about its practice. The information obtained from the questionnaire was coded, entered, and analyzed using IBM SPSS version 19.A total of 170 questionnaires were returned within the stipulated time frame with response rate of 66.7%. Majority, (135, 86%) respondents felt palliative care was about the active management of the dying while 70.5% of respondents equated palliative care to pain management. Regarding the philosophy of palliative care, 70 (57.9%) thought that it affirms life while 116 (78.4%) felt palliative care recognizes dying as a normal process. One hundred and twenty-two (78.7%) respondents were of the opinion that all dying patients would require palliative care. The patient should be told about the prognosis according to 122 (83%) respondents and not doing so could lead to lack of trust (85%). Regarding the area of opioid use in palliative care, 76% of respondents agreed that morphine improves the quality of life of patients.There are plausible gaps in the knowledge of the healthcare workers in the area of palliative care. Interventions are needed to improve their capacity.
- β-arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Mar 6.
Tolerance to the behavioural effects of morphine is blunted in β-arrestin-2 knockout mice but opioid withdrawal is largely unaffected. The cellular mechanisms of tolerance have been studied in some neurons from β-arrestin-2 knockouts but tolerance and withdrawal mechanisms have not been examined at the cellular level in periaqueductal grey (PAG) neurons, which are crucial for central tolerance and withdrawal phenomena.μ-Opioid receptor (MOPr) inhibition of voltage-gated calcium channel currents (ICa ) was examined by patch clamp recordings from acutely dissociated PAG neurons from wild-type and β-arrestin-2 knockout mice treated chronically with morphine (CMT) or vehicle. Opioid withdrawal-induced activation of GABA transporter (GAT-1) currents was determined using perforated patch recordings from PAG neurons in brain slices.MOPr inhibition of ICa in PAG neurons was unaffected by β-arrestin-2 deletion. CMT induced impaired coupling of MOPr to ICa in PAG neurons from wild-type mice but this cellular tolerance was not observed in neurons from CMT β-arrestin-2 knockouts. However, β-arrestin-2 knockouts displayed similar opioid-withdrawal induced activation of GAT-1 currents to wild-type PAG neurons.These results show that in β-arrestin-2 knockout mice, the central neurons involved in the anti-nociceptive actions of opioids also fail to develop cellular tolerance to opioids following chronic morphine. The results also provide the first cellular physiological evidence that opioid withdrawal is not disrupted by β-arrestin-2 deletion. However, the unaffected basal sensitivity to opioids in PAG neurons provides further evidence that changes in basal MOPr sensitivity cannot account for the enhanced acute nociceptive response to morphine reported in β-arrestin-2 knockouts.
- Dorsal Hippocampal NMDA Receptor Blockade Impairs Extinction of Naloxone-precipitated Conditioned Place Aversion in Acute Morphine-treated Rats by Suppressing ERK and CREB Phosphorylation in the Basolateral Amygdala. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Mar 6.
Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying extinction of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction.Naloxone-induced conditioned place aversion (CPA) of Sprague Dawley rats was used to measure conditioned aversion. N-methyl-D-aspartate (NMDA) receptor antagonist and mitogen-activated protein kinase kinase inhibitor were applied intracranial injections. The phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) was detected using Western blot.Extinction of CPA behavior induces an increase in ERK and CREB phosphorylation in the DH and the BLA, but not in the CeA. Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuates ERK and CREB phosphorylation in the BLA and impairs extinction of CPA behavior. Although intra-DH injections of AP-5 attenuates extinction training-induced activation of ERK-CREB pathway in the BLA, intra-BLA injection of AP5 have no effect on extinction training-induced activation of ERK-CREB pathway in the DH.These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behavior and that the DH, via a direct or indirect pathway, modulates activity of ERK and CREB in the BLA through activation of NMDA receptor after extinction training. Understanding the mechanisms underlying extinction of conditioned aversion could facilitate the treatment of drug addiction.
- Long-term administration of fluvoxamine attenuates neuropathic pain and involvement of spinal serotonin receptors in diabetic model rats. [Journal Article]
- Hiroshima J Med Sci 2013 Dec; 62(4):83-9.
Diabetic neuropathic pain management is difficult even with non-steroidal anti-inflammatory drugs and narcotic analgesics such as morphine. Fluvoxamine, a class of selective serotonin reuptake inhibitors (SSRIs), is widely used to treat depression. Its analgesic effects are also documented for diabetic neuropathic pain, but they are limited because it is administered as a single-dose. In this study, we examined the time course of the antiallodynic effect of fluvoxamine in a rat model of diabetic neuropathic pain, which was induced by a single intraperitoneal administration of streptozotocin (75 mg/kg). In addition, the involvement of spinal serotonin (5-HT) receptors in long-term fluvoxamine treatment was studied by intrathecal administration of 5-HT receptor antagonists. In this study the development of mechanical hyperalgesia was assessed by measuring the hind paw withdrawal threshold using von Frey filaments. The results demonstrated that daily oral administration of fluvoxamine (10, 30, and 100 mg/kg) to diabetic rats from 3 to 8 weeks after streptozotocin administration resulted in a dose-dependent antiallodynic effect. The antiallodynic effect was sustained from 2 to 5 weeks after fluvoxamine administration. The antiallodynic effect of fluvoxamine in the diabetic rats was attenuated by WAY-100635 (a 5-HT(1A) receptor antagonist) intrathecally administered 1 week after the onset of daily administration of fluvoxamine, whereas no significant attenuation was seen when the antagonist was administered 3 and 5 weeks after fluvoxamine administration. The antiallodynic effect of fluvoxamine was also attenuated by ketanserin (a 5-HT(2A/2C) receptor antagonist) and ondansetron (a 5-HT3 receptor antagonist) intrathecally administered 1 and 3 weeks after the onset of daily fluvoxamine administration. However, no significant attenuation was observed when the antagonist was administered 5 weeks after fluvoxamine administration. This study demonstrated that daily oral administration of fluvoxamine can afford a sustained antiallodynic effect against streptozotocin-induced neuropathic pain. Furthermore, there appears to be a time-dependent relevance of different types of 5-HT receptors (5-HT(1A), 5-HT(2A/2C), and 5-HT3) to streptozotocin-induced diabetic neuropathic pain when treated with daily fluvoxamine.
- Chromatographic Resolution of Closely Related Species: Drug Metabolites and Analogs. [JOURNAL ARTICLE]
- J Sep Sci 2014 Mar 4.
In this study, we investigate the separation of a variety of mixtures of drugs, metabolites and related analogs including representatives of the carbamazepine, methylated xanthine, steroid hormone, nicotine and morphine families using several automated chromatographic method development screening systems including ultrahigh performance liquid chromatography, Core-Shell HPLC, Achiral supercritical fluid chromatography (SFC) and Chiral SFC. Of the 138 column and mobile phase combinations examined for each mixture, a few chromatographic conditions afford the best overall performance, with a single achiral SFC method (4.6 × 250 mm, 3.0 μm GreenSep Ethyl Pyridine, 25 mM isobutylamine in methanol/CO2 ) affording excellent separation for all samples. Four of these mixtures were also resolved by achiral SFC on the Luna HILIC and chiral SFC Chiralpak IB columns using methanol or ethanol with 25 mM isobutylamine as polar modifiers. Modifications of standard chromatography screening conditions afforded fast separation methods (from 1 to 5 min) for baseline resolution of all components of each of these challenging sets of closely related compounds. This article is protected by copyright. All rights reserved.
- Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine. [JOURNAL ARTICLE]
- Org Biomol Chem 2014 Mar 4.
As the most active metabolite of heroin, 6-monoacetylmorphine (6-MAM) can penetrate into the brain for the rapid onset of heroin effects. The primary enzymes responsible for the metabolism of 6-MAM to the less potent morphine in humans are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The detailed reaction pathways for AChE- and BChE-catalyzed hydrolysis of 6-MAM to morphine have been explored, for the first time, in the present study by performing first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the two enzymatic reaction processes follow similar catalytic reaction mechanisms, and the whole catalytic reaction pathway for each enzyme consists of four reaction steps. According to the calculated results, the second reaction step associated with the transition state TS2(a)/TS2(b) should be rate-determining for the AChE/BChE-catalyzed hydrolysis, and the free energy barrier calculated for the AChE-catalyzed hydrolysis (18.3 kcal mol(-1)) is 2.5 kcal mol(-1) lower than that for the BChE-catalyzed hydrolysis (20.8 kcal mol(-1)). The free energy barriers calculated for the AChE- and BChE-catalyzed reactions are in good agreement with the experimentally derived activation free energies (17.5 and 20.7 kcal mol(-1) for the AChE- and BChE-catalyzed reactions, respectively). Further structural analysis reveals that the aromatic residues Phe295 and Phe297 in the acyl pocket of AChE (corresponding to Leu286 and Val288 in BChE) contribute to the lower energy of TS2(a) relative to TS2(b). The obtained structural and mechanistic insights could be valuable for use in future rational design of a novel therapeutic treatment of heroin abuse.
- Clinical Pharmacokinetics of Morphine and Its Metabolites During Morphine Dose Titration for Chronic Cancer Pain. [JOURNAL ARTICLE]
- Ther Drug Monit 2014 Feb 28.
Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay.Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h·kg; the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively).This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.
- Female rat hippocampal cell density after conditioned place preference. [Journal Article]
- Folia Biol (Praha) 2014; 60(1):47-51.
The hippocampus is important for learning tasks, such as conditioned place preference (CPP), which is widely used as a model for studying the reinforcing effects of drugs with dependence liability. Long-term opiate use may produce maladaptive plasticity in the brain structures involved in learning and memory, such as the hippocampus. We investigated the phenomenon of conditioning with morphine on the cell density of female rat hippocampus. Forty-eight female Wistar rats weighing on average 200-250 g were used. Rats were distributed into eight groups. Experimental groups received morphine daily (three days) at different doses (2.5, 5, 7.5 mg/kg) and the control-saline group received normal saline (1 ml/kg), and then the CPP test was performed. Three sham groups received only different doses (2.5, 5, 7.5 mg/kg) of morphine without CPP test. Forty-eight hours after behavioural testing animals were decapitated under chloroform anaesthesia and their brains were fixed, and after tissue processing, slices were stained with cresyl violet for neurons and phosphotungstic acid haematoxylin for astrocytes. The maximum response was obtained with 5 mg/kg of morphine. The density of neurons in CA1 and CA3 areas of hippocampus after injection of morphine and CPP was decreased. The number of astrocytes in different areas of hippocampus was increased after injection of morphine and CPP. It seems that the effective dose was 5 mg/kg, as it led to the CPP. We concluded that both injection of mor phine and CPP can decrease the density of neurons and also increase the number of astrocytes in the rat hippocampus.