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N 6 -clyclohexyladenosine (CHA) is an adenosine A 1 receptor agonist that inhibits thermogenesis. Cardiovascular side effects however, limit use of CHA as a therapeutic. We and others have shown that this can be reversed by administering 8-p-(sulfophenyl)theophylline (8-SPT), a nonspecific antagonist that does not cross the BBB. Other evidence shows that CNS actions of CHA may contribute to bradycardia through enhanced vagal tone and other mechanisms. Here we test the hypothesis that 8-SPT pretreatment alone is sufficient to prevent hypotension caused by CHA. To test this hypothesis, we pretreated rats with 8-SPT alone, and in combination with other antagonists to test the hypothesis that direct action of CHA on the heart is the primary mechanism by which CHA induces bradycardia and hypotension. Results show that pretreatment with 8-SPT alone is not sufficient to prevent CHA-induced hypotension. Pretreatment with 8-SPT or atropine alone did not prevent the fall in mean arterial pressure (MAP) and heart rate (HR), however, pretreatment with 8-SPT (25 mg/kg) and atropine (1 mg/kg) 15 min before CHA (1 mg/kg) preserves MAP and HR baseline values after CHA administration. We next asked if blood pressure was managed during the transition into a hypometabolic state, would prolong CHA-mediated inhibition of metabolism after cardiac arrest improve outcome better than anti-shivering medications meperidine and buspirone. We found that CHA-mediated hypotension can be mitigated by pretreatment with atropine and 8-SPT. This combination administered after cardiac arrest facilitated temperature management and metabolic suppression better than meperidine and buspirone, however, did not improve survival., Competing Interests: Declaration of competing interest Kelly Drew has a financial interest in Be Cool Pharmaceutics. Kelly Drew and Bernard Laughlin hold intellectual property for technology related to formulation. For other authors the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Infertility caused by drugs that inhibit serotonin reuptake has been attributed to serotonin toxicity. Serotonin has been linked to cause a rise in prolactin and cortisol. This study examined the effects of meperidine, sertraline, tianeptine and combinations on female rat reproductive function., Methods: Female rats were split into 8 groups (n=7): healthy control (HG), meperidine (MG), sertraline (SG), tianeptine (TG), meperidine+sertraline (MSG), meperidine+tianeptine (MTG), sertraline+tianeptine (STG), meperidine+sertraline+tianeptine (MSTG). Meperidine (20 mg/kg, 2×1) was injected intramuscularly. Sertraline (30 mg/kg, 1×1) and tianeptine (5 mg/kg, 1×1) were given orally. The HG received distilled water as solvent. Treatments continued for 20 days. Then, adult males were added to the rat groups and drug treatment continued for another five days. Blood samples were collected on day 26 for biochemical tests., Results: Total oxidant status (TOS) and total antioxidant status (TAS) were not statistically significant between groups (p>0.05). Meperidine (p<0.001) and sertraline (p<0.001) alone increased prolactin levels in comparison to HG and tianeptine inhibited the increase (p<0.001). While meperidine increased corticosterone levels versus HG (p<0.001), sertraline and tianeptine were close to HG (p>0.05). Number of infertile animals was 6 for meperidine, 3 for sertraline, and none for tianeptine. While the duration of pregnancy in MG (15 days) and SG (15 days) was longer compared to HG (2.86 days), no change was observed in TG (2.5 days)., Conclusion: Tianeptine and other serotonin re-uptake stimulants may be useful in the treatment of reproductive dysfunction and infertility due to serotonin re-uptake inhibitor treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Recently, use of HT35 receptor antagonists to prevent postoperative shivering has attracted a great deal of attention. This study was conducted with the aim of investigating the effectiveness of granisetron as an HT35 antagonist when compared with ondansetron and meperidine in preventing postoperative shivering., Material and Methods: In this triple blind random clinical trial study, 90 patients 18-50 years of age with ASA Class I and II undergoing general anesthesia were randomly assigned into one of the three drug groups: O (4-mg ondansetron), G (40 μg/kg of granisetron), and P (25 mg meperidine), immediately before induction of anesthesia. After anesthesia induction, at the end of the surgery, after the entrance and after leaving the recovery state, central temperature, peripheral temperature, heart rate, systolic blood pressure, diastolic blood pressure, and shivering were measured and documented. Two-tailed P < 0.05 was considered significant., Results: In the meperidine, ondansetron, and granisetron groups, 4 (13.3%), 3 (10%), and 10 (33.3%) of patients experienced shivering during recovery, where the difference between the ondansetron and granisetron groups was significant (p-value=0.02). The variations in the mean arterial pressure during the investigation stages only in the ondansetron group were not significant (p>0.05). At the beginning of recovery, the reduction of peripheral temperature significantly was lower in the ondansetron group (p<0.05), while reduction of the central temperature was significantly (p<0.05) higher in the granisetron group. By the end of the recovery, the variations in the peripheral temperature across the three groups were consistent with the changes at the beginning of recovery, but variations of the central temperature across the three groups was not significantly diverse., Conclusion: Granisetron was not found to be much effective in preventing postoperative shivering. Ondansetron and meperidine were equally effective in preventing postoperative shivering. Ondansetron also causes less hemodynamic changes compared to other drugs, while granisetron is more effective in terms of preventing nausea and vomiting.

Background: Shivering is one of the most common adverse outcomes associated with the administration of spinal anaesthesia, which, when clinically relevant, leads to numerous detrimental effects on the human body. Hence, its management becomes imperative. Meperidine, an opioid analgesic, is the drug of choice for this condition. However, the use of meperidine is controversial, as it carries the devastating adverse effect of respiratory depression. We explored the role of granisetron, a 5HT3 antagonist and a commonly used antiemetic premedication, in minimising the incidence of post-spinal shivering and decreasing the use of meperidine as a rescue drug., Methods: Overall, 160 parturient patients, between the ages 18-50, undergoing uncomplicated, elective caesarean section, were enrolled in the study, and randomized into two groups with 80 participants each: Group A received 3ml of normal saline, and Group B was administered 3 mg granisetron,15 minutes before spinal anaesthesia institution. Incidence of clinically relevant shivering (score of 3 or more) was noted, and it was recorded whether meperidine was used or not., Results: 67.5% of participants in Group A, and 32.5% of patients in Group B, experienced clinically relevant shivering, with 62.5% of patients in Group A and 28.75% in Group B warranting the use of meperidine. There was a statistically significant difference between the two groups in terms of incidence of clinically relevant shivering, and meperidine consumption (p-value <0.001)., Conclusions: Premedication with 3 mg granisetron effectively attenuates the occurrence of post-spinal shivering and, hence, lowers the requirement of meperidine as rescue medication.

Background: Several adjuvants, added to local anesthetics, were suggested to induce an ideal regional block with high-quality analgesia. The purpose of this study was to evaluate the particular blocking properties of low-dose bupivacaine in combination with meperidine and fentanyl in spinal anesthesia during Cesarean sections., Methods: A randomized, double-blind clinical trial was conducted at Hafez Hospital affiliated with Shiraz University of Medical Sciences (Shiraz, Iran) from February 2015 to February 2016. A total of 120 pregnant women, who underwent spinal anesthesia during elective Cesarean section were enrolled in the study. Based on block-wise randomization, the patients were randomly assigned to three groups, namely "B" group received 2 mL bupivacaine 0.5% (10 mg), "BM" group received 8 mg bupivacaine and 10 mg meperidine, and "BF" group received 8 mg bupivacaine and 15 µg fentanyl intrathecally. The block onset, the duration of analgesia, and the time of discharge from the post-anesthesia care unit (PACU) were all assessed. Data were analyzed using SPSS software version 21, and P<0.05 were considered statistically significant., Results: The mean duration of motor blocks in the B group (150 min) were significantly higher than the BM (102 min) and BF (105 min) groups (P<0.0001). In both the BM and BF groups, the duration of sensory and motor blocks was the same. The length of stay in the PACU was significantly longer in the B group (P<0.001) than the BM and BF groups. When meperidine or fentanyl was added to bupivacaine, the duration of the analgesia lengthened (P<0.001)., Conclusion: Intrathecal low-dose spinal anesthesia induced by bupivacaine (8 mg) in combination with meperidine and/or fentanyl for Cesarean section increased maternal hemodynamic stability, while ensuring effective anesthetic conditions, extending effective analgesia, and reducing the length of stay in PACU. Trial Registration Number: IRCT2015013119470N14., Competing Interests: None declared., (Copyright: © Iranian Journal of Medical Sciences.)

Objective: Catheter-related bladder discomfort (CRBD) is a common complication of intraoperative urinary catheterization. Various studies have evaluated the efficacy of different interventions in postoperative CRBD. The present review was performed to assess the efficacy of these interventions., Methods: PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were systematically searched to identify randomized controlled trials (RCTs) investigating the efficacy of different drugs for the prevention of postoperative CRBD. This review evaluated the incidence and severity of CRBD after different interventions at 0, 1, 2, and 6 h postoperatively., Results: Forty-five studies including 31 different drugs were analyzed. Eleven drugs were investigated in more than two RCTs, of which dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and pudendal nerve block (PNB) generally showed significantly higher efficacy than controls postoperatively. Solifenacin only showed significant efficacy compared with the control at 0 h, and intravenous lidocaine only showed significant efficacy compared with the control at 6 h. There were insufficient trials to draw conclusions regarding atropine, butylscopolamine, chlorpheniramine, clonidine, darifenacin, diphenhydramine, glycopyrrolate, intravesical bupivacaine, ketamine-haloperidol, pethidine-haloperidol, ketorolac, lidocaine-prilocaine cream, magnesium, hyoscine n-butyl bromide, oxycodone, paracetamol, parecoxib, trospium, resiniferatoxin, or amikacin. However, all but pethidine-haloperidol and chlorpheniramine showed some efficacy at various time points compared with controls., Conclusion: This review suggests that dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and PNB are effective in preventing postoperative CRBD. Considering the efficacy and adverse effects of all drugs, dexmedetomidine and gabapentin were ranked best., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Meperidine (pethidine) is a µ-opioid receptor (MOR) agonist widely used in the treatment of cancer pain. While MOR agonists in experimental models have demonstrated both pro- and antitumorigenic properties, meperidine has unique features which may be predominantly anticancer in nature. Meperidine both inhibits NMDA (N-methyl-D-Aspartate) receptors, which are involved in the progression of glioblastoma, and blocks NADH:Ubiquinone Oxidoreductase, which may hinder mitochondrial respiration. In the developing embryonic neural tissue, meperidine reduces cell proliferation around the neural tube and lowers the expression of the B RE (brain and reproductive organ-expressed). This is notable given that the B RE gene is implicated in cancer chemoresistance and gliomagenesis. Further, meperidine inhibits P-glycoprotein, which is involved in cancer multidrug resistance and the degradation of the sphingolipid backbone, ceramide. By enhancing the pro-autophagic and pro-apoptotic ceramide levels in cancer cells, meperidine stimulates cell death and reverses multidrug resistance. Tamoxifen, a safe medication employed in the treatment of breast cancer, directly blocks P-glycoprotein and boosts levels of ceramide both via inhibition of glycosylceramide synthase and ceramidase. Further, tamoxifen blocks NMDA-neurotoxicity and therefore it may act synergistically with meperidine in reducing glioblastoma progression associated with NMDA-activation. Finally, tamoxifen blocks glycolysis which may enhance the mitochondrial-blocking activity of meperidine to shut down energy metabolism of glioblastoma cells. Because of these properties, we believe that the combination of meperidine and tamoxifen merits study in cell culture and animal models to investigate a potential synergistic relationship in the treatment of glioblastoma., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Post-anesthetic shivering is one of the most common complications after anesthesia. Ketamine has been considered to be an effective treatment for post-anesthetic shivering, but the evidence for its therapeutic benefit after spinal anesthesia is limited. The aim of this study was to compare the effects of intravenous ketamine with intrathecal meperidine in the prevention of post-anesthetic shivering after spinal anesthesia for lower limb orthopedic surgeries., Methods: In a double-blind randomized parallel-group clinical trial, a total of 150 patients scheduled for lower limb orthopedic surgeries under spinal anesthesia were selected and randomly divided into three equally sized groups of intravenous ketamine (0.5 mg/kg), intrathecal meperidine (0.2mg/kg) or intravenous normal saline (as placebo). The intensity of shivering in patients were evaluated during surgery and after transfer into the post anesthesia care unit. Also, changes in patients' drowsiness, nausea, vomiting, pruritus, mean arterial pressure, heart rate, and arterial oxygen saturation (SPO2) during surgery and until the end of anesthesia were evaluated., Results: In all times of evaluation (20, 60, 80, 100 and 120 minutes after onset of spinal anesthesia) patients in control group showed a greater intensity of shivering compared to other groups. However, patients who received intrathecal meperidine experienced significantly lower intensity of post anesthetic shivering (p<0.05). The results showed a significant mean arterial pressure and heart rates differences between the three groups, only on 20 and 60 minutes after initiation of spinal anesthesia. The incidence of nausea, vomiting, and pruritus was not significantly different in all three groups, although all patients who received ketamine experienced drowsiness after surgery (p<0.001)., Conclusion: The results of the present study showed that, although both intrathecal meperidine and intravenous ketamine could effectively prevent postoperative shivering after spinal anesthesia in lower limb orthopedic surgeries, intrathecal meperidine was associated with more efficacy benefits and a lower frequency of side effects such as post-anesthesia drowsiness., (© 2021 Gholinataj A. et al.)

Objective: To describe the pharmacokinetics and pharmacodynamics of meperidine after IM and subcutaneous administration in horses., Study Design: prospective, randomized, blinded, crossover trial., Animals: Six adult horses weighing 494 ± 33 kg., Methods: Treatments included meperidine 1 mg/kg IM with saline 6 mL subcutaneously, meperidine 1 mg/kg subcutaneously with saline 6 mL IM, and saline 6 mL subcutaneously and 6 mL IM, with a 7-day washout between treatments. Plasma meperidine concentrations and pharmacodynamic values (thermal and mechanical thresholds, physiological variables, fecal production) were collected at various time points for 24 hours. Accelerometry data were obtained for 8 hours to measure locomotor activity. Data were analyzed with a mixed effects model, and α was set at .05., Results: Meperidine terminal half-life (T 1/2 ), maximal plasma concentrations, and time to maximal concentration were 186 ± 59 and 164 ± 56 minutes, 265.7 ± 47.2 and 243.1 ± 80.1 ng/mL at 17 ± 6, and 24 ± 13 minutes for IM at subcutaneous administration, respectively. No effect of treatment or time was observed on thermal or mechanical thresholds, heart rate, respiratory rate, locomotor activity, frequency of defecations, or fecal weight (P > .2 for all)., Conclusion: Maximum meperidine concentrations were achieved quickly with a short T 1/2 in both treatment groups. Neither IM nor subcutaneous meperidine influenced thermal or mechanical threshold or physiological variables., Clinical Significance: The short half-life and lack of detectable antinociceptive effect do not support IM or subcutaneous administration meperidine at 1 mg/kg for analgesia in horses., (© 2020 American College of Veterinary Surgeons.)

Background: Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated., Results: Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg)., Conclusions: Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.

Bacterial pore-forming toxin aerolysin-like proteins (ALPs) are widely distributed in animals and plants. However, functional studies on these ALPs remain in their infancy. βγ-CAT is the first example of a secreted pore-forming protein that functions to modulate the endolysosome pathway via endocytosis and pore formation on endolysosomes. However, the specific cell surface molecules mediating the action of βγ-CAT remain elusive. Here, the actions of βγ-CAT were largely attenuated by either addition or elimination of acidic glycosphingolipids (AGSLs). Further study revealed that the ALP and trefoil factor (TFF) subunits of βγ-CAT bind to gangliosides and sulfatides, respectively. Additionally, disruption of lipid rafts largely impaired the actions of βγ-CAT. Finally, the ability of βγ-CAT to clear pathogens was attenuated in AGSL-eliminated frogs. These findings revealed a previously unknown double binding pattern of an animal-secreted ALP in complex with TFF that initiates ALP-induced endolysosomal pathway regulation, ultimately leading to effective antimicrobial responses., Competing Interests: The authors declare no competing interests.

Aim: To evaluate the safety, effect on breastfeeding and efficacy of a combination of pethidine and levallorphan (Pethilorfan) for pain relief during labor., Methods: We compared maternal or neonatal morbidities, suckling difficulties in newborns and breastfeeding rates between 177 women who received 50-200 mg (as pethidine) of Pethilorfan during labor (Pethilorfan group) and 354 women who delivered their infants without analgesic drugs immediately before or after each woman in the Pethilorfan group (control group) from January 1, 2005 to December 31, 2016. We performed univariate and multivariate analyses for comparison between the two groups. We also evaluated the efficacy of Pethilorfan retrospectively., Results: The Pethilorfan group included more women with prolonged and/or operative deliveries than the control group. Nevertheless, no significant differences were seen between the two groups in the rates of Apgar scores less than 7 at 1 or 5 min, composite neonatal morbidities, hyperbilirubinemia or respiratory disturbances. The incidence of suckling difficulties lasting over 24 h and the breastfeeding rates at discharge or after 1 month were also similar. Maternal adverse effects of Pethilorfan were generally mild and transient. The efficacy ratio of Pethilorfan was 83.6%, although its analgesic effect was usually incomplete., Conclusion: Pethilorfan can be used safely for labor pain relief without increasing maternal or neonatal morbidities, or impeding breastfeeding, if it is administered at a prudent dosage. Parenteral opioids including Pethilorfan should remain as an option for treating women in labor pain, particularly when epidural analgesia is not readily available or contraindicated., (© 2018 Japan Society of Obstetrics and Gynecology.)

Background: About a third of women receiving pethidine for labour pain subsequently require an epidural, which provides effective pain relief but increases the risk of instrumental vaginal delivery. Remifentanil patient-controlled analgesia (PCA) in labour is an alternative to pethidine, but is not widely used. We aimed to evaluate epidural analgesia progression among women using remifentanil PCA compared with pethidine., Methods: We did an open-label, multicentre, randomised controlled trial in 14 UK maternity units. We included women aged 16 years or older, beyond 37 weeks' gestation, in labour with a singleton cephalic presentation, and who requested opioid pain relief. We randomly assigned eligible participants (1:1) to either the intravenous remifentanil PCA group (40 μg bolus on demand with a 2 min lockout) or the intramuscular pethidine group (100 mg every 4 h, up to 400 mg in 24 h), using a web-based or telephone randomisation service with a minimisation algorithm for parity, maternal age, ethnicity, and mode of labour onset. Because of the differences in routes of drug administration, study participants and health-care providers were not masked to the group allocation. The primary outcome was the proportion of women who received epidural analgesia after enrolment for pain relief in labour. Primary analyses were unadjusted and analysed by the intention-to-treat principle. This study is registered with the ISRCTN registry, number ISRCTN29654603., Findings: Between May 13, 2014, and Sept 2, 2016, 201 women were randomly assigned to the remifentanil PCA group and 200 to the pethidine group. One participant in the pethidine group withdrew consent, leaving 199 for analyses. The proportions of epidural conversion were 19% (39 of 201) in the remifentanil PCA group and 41% (81 of 199) in the pethidine group (risk ratio 0·48, 95% CI 0·34-0·66; p<0·0001). There were no serious adverse events or drug reactions directly attributable to either analgesic during the study., Interpretation: Intravenous remifentanil PCA halved the proportion of epidural conversions compared with intramuscular pethidine. This finding challenges routine pethidine use as standard of care in labour., Funding: National Institute for Health Research Clinician Scientist Award., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Aims: A common limiting factor in the throughput of gastrointestinal endoscopy units is the availability of space for patients to recover post-procedure. This study sought to identify predictors of abnormally long recovery time after colonoscopy performed with procedural sedation. In clinical research, this type of study would be performed using only one regression modeling approach. A goal of this study was to apply various "machine learning" techniques to see if better prediction could be achieved., Methods: Procedural data for 31,442 colonoscopies performed on 29,905 adult patients at Massachusetts General Hospital from 2011 to 2015 were analyzed to identify potential predictors of long recovery times. These data included the identities of hospital personnel, and the initial statistical analysis focused on the impact of these personnel on recovery time via multivariate logistic regression. Secondary analyses included more information on patient vitals both to identify secondary predictors and to predict long recoveries using more complex techniques., Results: In univariate analysis, the endoscopist, procedure room nurse, recovery room nurse, and surgical technician all showed a statistically significant relationship to long recovery times, with p-value below 0.0001 in all cases. In the multivariate logistic regression, the most significant predictor of a long recovery time was the identity of the recovery room nurse, with the endoscopist also showing a statistically significant relationship with a weaker effect. Complex techniques led to a negligible improvement over simple techniques in prediction of long recovery periods., Conclusion: The hospital personnel involved in performing a colonoscopy show a strong association with the likelihood of a patient spending an abnormally long time recovering from the procedure, with the most pronounced effect for the nurse in the recovery room. The application of more advanced approaches to improve prediction in this clinical data set only yielded modest improvements., Competing Interests: The authors have declared that no competing interests exist. UK and KN confirm that the commercial affiliation with IBM does not alter their adherence to all PLOS ONE policies on sharing data and materials.

Background: Sedatives or analgesics are widely used to relieve a patient's discomfort during colonoscopy (CS). Although cardiopulmonary adverse events are sometimes experienced during the examination, the risk factors for vital signs fluctuation (VSF) have not been fully elucidated. This study thus aimed to identify the risk factors for VSF during the examination, as well as to evaluate the frequency and the degree of VSF., Summary: A total of 755 consecutive subjects who received CS under endoscopist-administrated sedation using midazolam, meperidine, or combination of both were retrospectively analyzed. We assessed the distribution of vital signs during the procedure and frequency of VSF. To identify independent risk factors, we analyzed the association between VSF and subjects' characteristics and procedure information using the multivariate logistic regression model. Consequently, VSF was observed in 17% of all; hypotension and oxygen desaturation was observed in 13 and 5%, respectively. However, we could achieve the purpose of all procedure and, no one required hospitalization or extension of hospital stay. Multivariate analysis revealed that age (OR 1.05 [95% CI 1.04-1.07]), being female (OR 1.78 [95% CI 1.19-2.70]), and use of midazolam (OR 5.06 [95% CI 3.18-8.08]) were independent risk factors for VSF., (© 2017 S. Karger AG, Basel.)

Objective: To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia., Design: A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire., Setting: A tertiary and regional maternity unit in South Australia., Findings: Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement., Key Conclusions: Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects., Implications for Practice: For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to compare the effectiveness of two sedative regimens, a benzodiazepine with either meperidine or fentanyl, in relieving pain in patients with cervical cancer undergoing intracavitary brachytherapy in terms of pain score and quality of life., Methods: Forty unselected outpatients undergoing brachytherapy (160 fractions) were enrolled with informed consent and randomized to receive a benzodiazepine with either meperidine or fentanyl. The perceived pain score according to a standard 10-item numeric rating scale was collected every 15 min during the procedure, and the perceived quality of life was determined at the end of each procedure using the EuroQol five-dimension questionnaire. The patients and medical staff members directly involved with the procedure were blinded to the medication used., Results: The patients' pain levels were mild in both analgesic groups. Meperidine appeared to be slightly more effective than fentanyl, although the differences in the average pain score and quality of life were not statistically significant., Conclusion: Both meperidine and fentanyl in combination with benzodiazepine were effective in relieving pain and discomfort in patients undergoing brachytherapy., Trial Registration: NCT02684942, ClinicalTrials.gov.

Background: Pain is a common problem which the patients in emergency departments (ED) face, especially trauma patients under treatment may suffer from physical, psychological and ethical issues. The purpose of this study was to evaluate traumatic pain management in the emergency department at a public hospital in Iran in 2014., Methods: This observational prospective study was conducted on 450 trauma patients admitted to a trauma emergency department. The tool used in this study has three parts: demographic data, data of trauma, and VRS (Verbal Rating Scales) score at a 7-point scale-at the arrival time to 4h later. The statistical analysis was conducted by using Mann-Whitney and Kruskal-Wallis tests, repeated measures, survival analysis, and multiple regression analysis., Results: The majority of the samples were male (83.3%) with the mean age of 35.2years. The patients mostly suffered from contusions and strains (42.4%). The majority of the patients [274 patients (60.8%)] received no intervention for pain relief and only 60 patients (13.3%) received analgesics. The mean time period of the first analgesic utilization was 41 (±20.4) minutes. Pain in admission, pain assessment, and receiving intervention could explain the 32% of pain reduction. No other variables such as age, sex, education, kind of trauma, and the shift of admission were involved in pain reduction., Conclusions: This research study demonstrated that comprehensive, adequate pain management remains an obscure goal within the emergency nursing setting. There is a need to undertake further research and develop educational programs on effective analgesic practice in pain management., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment. Western blotting revealed that PC3-PR cells expressed higher levels of sphingosine kinase 1 (SPHK1) and glucosylceramide synthase (GCS) but lower levels of acid sphingomyelinase (ASMase) and neutral sphingomyelinase 2 than did PC3 cells. Inhibition of SPHK1 using siRNA or a pharmacological inhibitor decreased S1P levels in PC3-PR cells and inhibited proliferation in the presence or absence of PTX, suggesting that SPHK1 is at least partially responsible for PTX resistance. Similarly, GCS inhibitors (PDMP and PPMP) increased cellular ceramides and suppressed the proliferation of PC3-PR. However, inhibition of proteasome function or histone deacetylase activity increased SMase and ceramide levels and suppressed PC3-PR proliferation. These results suggest that modulation of metabolic enzyme expression and alteration of the sphingolipid rheostat protects cancer cells against PTX., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Postoperative pain due to tissue damage caused during surgery not only causes discomfort for the patients, but can also result in prolonged hospitalization, increased morbidity and respiratory disorders, and readmission to the hospital. For postoperative pain control, numerous methods and medications have been suggested, such as non-steroidal anti-inflammatory drugs (NSAIDs) and narcotics. Pethidine, as a narcotic analgesic, and ketorolac, as an NSAID, are widely used for pain control. Thus, in this study, the effects of these two drugs were studied and compared in terms of pain control after inguinal hernia surgery in children of 1-12 years of age., Materials and Methods: Sixty-six children undergoing inguinal herniorrhaphy were selected and randomly divided into 2 groups. The first group received 0.5 mg/kg ketorolac and the second group received 1 mg/kg pethidine during extubation. Postoperative pain (using Wong Baker pain scale) and complications were measured until 24 hours after surgery., Results: Mean and standard deviations of postoperative pain 1 hour after surgery in the pethidin and ketorolac groups were 5.06 ± 1.41 and 3.88 ± 0.93, respectively. The scale was significantly lower in the ketorolac group (P < 0.001). Postoperative pain intensity 2 hours after surgery in these two groups was 4.48 ± 1.52 and 3.55 ± 1.15, respectively, and the difference between the two groups was significant (P = 0.006). The variation in postoperative pain intensity in the ketorolac group was statistically lower than the pethidin group (P = 0.020). CONCLUSION.

Esophageal cancer is one of the least studied and deadliest cancers worldwide with a poor prognosis due to limited options for treatment. Chemotherapy agents such as the microtubule-targeting compounds are the mainstay of palliation for advanced esophageal cancer treatment. However, the toxicity and side effects of tubulin-binding agents (TBAs) have promoted the development of novel, more potent but less toxic TBAs. Herein, we identified 2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop-2-en-1-yl)oxy] phenol (PPMP) as a novel TBA for esophageal cancer treatment. PPMP markedly inhibited tubulin polymerization, and decreased viability and anchorage-independent growth of esophageal cancer cell lines, effects that were accompanied by G2/M arrest and apoptosis. Importantly, we produced patient-derived esophageal cancer xenografts to evaluate the therapeutic effect of PPMP in a setting that best mimics the clinical context in patients with esophageal cancer. Overall, we identified PPMP as a novel microtubule-destabilizing compound and as a new therapeutic agent against esophageal carcinoma., Competing Interests: The authors declare no conflicts of interest.

Background: The optimum dose of dexmedetomidine for shivering control with the least hemodynamic derangements is still under research., Objective: To compare the efficacy, hemodynamic and side effects of dexmedetomidine in 3 different doses with those of meperidine for the treatment of shivering in patients undergoing spinal anesthesia for minor elective lower abdominal surgery., Study Design: Prospective double-blind randomized clinically controlled study., Setting: University hospital., Methods: One hundred twenty patients who developed shivering under spinal anesthesia.On shivering, patients were randomly allocated to receive an intravenous 2 mL bolus dose of meperidine 0.4 mg/kg (meperidine group, n = 30), dexmedetomidine 0.5 µg/kg (DEX I group, n = 30), 0.3 µg/kg (DEX II group, n = 30), or 0.2µg/kg (DEX III group, n = 30). Control of shivering, time taken for cessation of shivering, response rate, recurrence, hemodynamic changes, sedation score, tympanic temperature, and side effects were noted and compared between groups., Results: The groups were comparable regarding demographic profile, tympanic temperature decline, and shivering onset time (P > 0.05). Lower shivering cessation time (P < 0.001) and higher response rate (P < 0.01) were observed in DEX I and II groups compared with DEX III and meperidine groups, with a nonsignificant difference between DEX I and II groups. Recurrence of shivering activity was higher in DEX III group (36.7%, P < 0.01) compared with DEX I (10%), DEX II (6.7%) and meperidine (16.7%) groups. Lower heart rates, systolic and diastolic blood pressure mean values were recorded in DEX I group (P < 0.05). Nine patients (30%) in DEX I group were in levels 3 - 5 of sedation (P < 0.02) compared with 5 (16.66%), 2 (6.66%), and 4 (13.3) patients in DEX II, DEX III, and meperidine groups, respectively., Limitations: This study is limited by its small sample size., Conclusions: Among the 3 doses investigated, dexmedetomidine 0.3µg/kg effectively treated shivering associated with spinal anesthesia with modest hemodynamic and sedation effects., Trial Registration: ClinicalTrials.gov Identifier: NCT02382432., Key Words: Dexmedetomidine, hypothermia, shivering, spinal anesthesia.

Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance., Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72h on expression and cisplatin cytotoxicity was tested., Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells., Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucosylceramide synthase (GCS) catalyzes the first committed step in the biosynthesis of glucosylceramide (GlcCer)-related glycosphingolipids (GSLs). Although inhibitors of GCS, PPMP and PDMP have been widely used to elucidate their biological function and relevance, our comprehensive literature review revealed that the available data are ambiguous. We therefore investigated whether and to what extent GCS inhibitors affect the expression of lactosylceramide (LacCer), neolacto (nLc4 and P1), ganglio (GM1 and GD3) and globo (Gb3 and SSEA3) series GSLs in a panel of human cancer cell lines using flow cytometry, a commonly applied method investigating cell-surface GSLs after GCS inhibition. Their cell-surface GSL expression considerably varied among cell lines and more importantly, sublethal concentrations (IC10) of both inhibitors preferentially and significantly reduced the expression of Gb3 in the cancer cell lines IGROV1, BG1, HT29 and T47D, whereas SSEA3 was only reduced in BG1. Unexpectedly, the neolacto and ganglio series was not affected. LacCer, the precursor of all GlcCer-related GSL, was significantly reduced only in BG1 cells treated with PPMP. Future research questions addressing particular GSLs require careful consideration; our results indicate that the extent to which there is a decrease in the expression of one or more particular GSLs is dependent on the cell line under investigation, the type of GCS inhibitor and exposure duration., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 μM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 μM, tramadol 20 μM, pethidine 30 μM, and ketamine 100 μM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.

Background: A variety of analgesic agents are available, and which one can be used in dogs and cats is a highly controversial issue, existing however a fear in the use of opiates due to possible adverse effects that these drugs can cause. The aim of this study was to compare the analgesic effect provided by the administration of tramadol or pethidine on early postoperative pain of cats undergoing ovariohysterectomy in a double-blind prospective study. Fourty-two animals were randomly assigned into three groups. Pet received pethidine (6 mg/kg), Tra 2 received tramadol (2 mg/kg) and Tra 4 received tramadol (4 mg/kg); all intramuscularly and associated with acepromazine (0.1 mg/kg). The efficacy of each analgesic regimen was evaluated prior to surgery (baseline - TBL), during surgery and 1, 3 and 6 hours after extubation with subjective pain scale, physiologic parameters, serum concentrations of glucose, cortisol and IL-6., Results: Changes in cardiovascular system were not clinically relevant. There were no significant differences in pain scores (P > 0.05) during the study, although the number of rescue analgesia was significantly higher (P < 0.05) at Pet group (5/14) than Tra 4 group (0/14), whereas in Tra 2, two animals (2/14) required additional analgesia. The serum cortisol values of Pet group were significantly higher at T1h T3h (P < 0.05) and T6h (P < 0.01) when compared to baseline (induction), also it was noticed a significant difference among the groups at T6h (Pet values were higher than Tra 2 and Tra 4; P < 0.05)., Conclusions: Tramadol provided adequate analgesia and it was more effective than pethidine to at least six hours for the studied animals. At the higher dose (4 mg/kg) tramadol is probably more effective, since rescue analgesia was not necessary. No significant changes were observed physiological parameter that could contraindicate the use of these opioid in described doses, for the feline species.

Aggregate-prone mutant proteins, such as α-synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate-prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol and Genz-123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant α-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease., (© 2014 International Society for Neurochemistry.)

Background: Labor pain is probably the most painful event in a woman's life. By the present consensus, epidural analgesia is the most effective and least depressive treatment for labor pain. Recent systematic reviews concluded that the risk of cesarean delivery or instrumental vaginal delivery for women receiving early epidural analgesia has not increased. However, studies designed for discussing this topic in Taiwan are few. In this study, the association of the intervention timing with labor outcomes in nulliparous women in Taiwan is discussed., Methods: We performed a retrospective chart review in parturients who underwent epidural analgesia for labor pain. Only nulliparae were included and divided into four groups based on the cervical dilatation width of 1, 2, 3, and 4 cm when they underwent epidural analgesia. We retrieved each patient's demographic characteristics, the course of labor and delivery, and the management of epidural analgesia from the medical chart., Results: A total of 799 nulliparae was included. The numbers of parturients with cervical dilatation width of 1, 2, 3, and 4 cm were 119, 338, 258, and 84 respectively. There was no significant difference in demographic factors, regimen of epidural analgesia, loading volume, and anesthesiologist in charge among the four groups. The percentages of cesarean delivery in the four groups were 27.73%, 20.71%, 15.89%, and 20.24%, respectively, and there was no significant difference among these four groups (p = 0.0651). The incidences of instrumental delivery in four groups were 13.51%, 14.59%, 18.65%, and 21.43% respectively, and there was no significant difference among these four groups either (p = 0.2278)., Conclusion: Our results revealed that the timing of epidural intervention affects neither the cesarean delivery rate nor the instrumental delivery rate on nulliparae in Taiwan with the cervical dilatation width ranging from 1 cm to 4 cm. The fear of increasing cesarean section rate after early epidural analgesia is unfounded. Women in labor can choose pain relief at any time., (Copyright © 2013. Published by Elsevier B.V.)

Lactosylceramide (LacCer) is a member of the glycosphingolipid family and is known to be a bioactive lipid in various cell physiological processes. However, the direct targets of LacCer and cellular events mediated by LacCer are largely unknown. In this study, we examined the effect of LacCer on the release of arachidonic acid (AA) and the activity of cytosolic phospholipase A2α (cPLA2α). In CHO-W11A cells, treatment with 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), an inhibitor of glucosylceramide synthase, reduced the glycosphingolipid level, and the release of AA induced by A23187 or platelet-activating factor was inhibited. The addition of LacCer reversed the PPMP effect on the stimulus-induced AA release. Exogenous LacCer stimulated the release of AA, which was decreased by treatment with an inhibitor of cPLA2α or silencing of the enzyme. Treatment of CHO-W11A cells with LacCer induced the translocation of full-length cPLA2α and its C2 domain from the cytosol to the Golgi apparatus. LacCer also induced the translocation of the D43N mutant of cPLA2α. Treatment of L929 cells with TNF-α induced LacCer generation and mediated the translocation of cPLA2α and AA release, which was attenuated by treatment with PPMP. In vitro studies were then conducted to test whether LacCer interacts directly with cPLA2α. Phosphatidylcholine vesicles containing LacCer increased cPLA2α activity. LacCer bound to cPLA2α and its C2 domain in a Ca(2+)-independent manner. Thus, we propose that LacCer is a direct activator of cPLA2α.

Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

The purpose of this study was to assess the clinical effects of dexmedetomidine, both alone and combined with pethidine or butorphanol, in cats. A prospective randomized blind study was performed. Thirty cats were randomly assigned to three groups of 10 animals: D: dexmedetomidine (20 μg/kg IM); DP: dexmedetomidine (10 μg/kg IM) and pethidine (2.5 mg/kg IM); DB: dexmedetomidine (10 μg/kg IM) and butorphanol (0.4 mg/kg IM). Quality of sedation, analgesia, muscle relaxation and the possibility of performing some clinical procedures were compared using a multifactorial scale. Sedation, analgesia and muscle relaxation increased progressively over time and did not differ in the three protocols. The three protocols facilitated the completion of several clinical procedures. The clinical variables studied showed a similar behaviour in the three protocols and remained close to the baseline, except for a drop in heart rate in protocol D. In conclusion, dexmedetomidine, either alone or combined with pethidine or butorphanol, offers suitable sedation, analgesia and relaxation to perform various clinical procedures in cats., (© 2012 Blackwell Publishing Ltd.)

Background: The efficacy of epidural anesthesia and analgesia in management of perioperative stress has been established. Perioperative pain management strategies decrease surgical complications and aid recovery. In this study, we aimed to document and compare the efficacy of epidural bupivacaine and intravenous meperidine on recovery of patients with elective abdominal aortic surgery performed under general anesthesia., Material and Methods: Patients undergoing elective abdominal aortic surgery between February 2009 and November 2011 were studied prospectively. Patients were randomized into epidural bupivacaine (n=40) and intravenous meperidine (n=40) groups regarding postoperative analgesia strategy. The preoperative demographic characteristics, perioperative outcomes, postoperative adverse effects of analgesia strategy, time to initiate oral intake, sedation scores, visual analogue scale results, and mobility scores were compared., Results: The mean ages of the patients were 61.7±8.1 in the epidural group and 59.4±9.7 in the intravenous group (p>0.05). The preoperative demographic characteristics of the patients were comparable between the groups. There were no statistically significant differences between groups regarding anesthesia times, intubation times, intensive care unit stay, hospital length of stay, postoperative vomiting, and postoperative cardiac, renal, and cerebral complications. Postoperative nausea was more prevalent in the meperidine group (p<0.05). In the epidural group, time to begin oral intake was shorter, sedation scores and visual analogue scale results were lower, and mobility scores were higher (p<0.05 each)., Conclusions: Epidural analgesia allowed earlier recovery compared to intravenous analgesia in patients undergoing elective abdominal aortic surgery, but did not affect postoperative outcomes and complications.

Background/aims: Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and glucosylceramide synthase (GCS) catalyzes ceramide metabolism. Increased ceramide levels have been suggested to enhance chemotherapy-induced death of cancer cells., Methods: Microarray and clinical data for ASM and GCS in astrocytomas WHO grade II-IV were acquired from the Rembrandt database. Moreover, the glioblastoma database of the Cancer Genome Atlas network (TCGA) was used for survival data of glioblastoma patients. For in vitro studies, increases in ceramide levels were achieved either by ASM overexpression or by the GCS inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) in human glioma cell lines. Combinations of alkylating chemotherapy or irradiation and ASM overexpression, PPMP or exogenous ceramide were applied in parental cells. The anti-glioma effects were investigated by assessing proliferation, metabolic activity, viability and clonogenicity. Finally, viability and clonogenicity were assessed in temozolomide (TMZ)-resistant cells upon treatment with PPMP, exogenous ceramide, alkylating chemotherapy, irradiation or their combinations., Results: Interrogations from the Rembrandt and TCGA database showed a better survival of glioblastoma patients with low expression of ASM or GCS. ASM overexpression or PPMP treatment alone led to ceramide accumulation but did not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PPMP or exogenous ceramide induced acute cytotoxicity in glioblastoma cells. Combined treatments with chemotherapy or irradiation led to additive, but not synergistic effects. Finally, no synergy was found when TMZ-resistant cells were treated with exogenous ceramide or PPMP alone or in combination with TMZ or irradiation., Conclusion: Modulation of intrinsic glioma cell ceramide levels by ASM overexpression or GCS inhibition does not enhance the anti-glioma activity of alkylating chemotherapy or irradiation.

Background: Hypothermia is a promising experimental treatment for acute ischemic stroke. Human trials are still at an early stage, with the focus now on using hypothermia in awake patients. Pethidine (meperidine) is the principle agent used to control shivering in humans; however, whether it has any modulating effects on the neuroprotective efficacy of hypothermia is unknown., Aim: The aim of this study was to determine if pethidine influences the neuroprotective effect of hypothermia in experimental stroke., Methods: Seventy-two male spontaneously hypertensive rats were anesthetized with isoflurane and randomly assigned to either normothermia (37. 4 °C rectal temperature); hypothermia (33 °C maintained for 130 mins); normothermia plus pethidine (2.5 mg/kg); or hypothermia plus pethidine. Temporary (90 mins) endovascular occlusion of the middle cerebral artery was induced blinded to treatment allocation and was confirmed with laser Doppler flowmetry. Pethidine and cooling were started immediately after vessel occlusion. Animals in the normothermia group had active temperature management using a heat lamp and fan. Assessments of outcome were carried out 24 after the induction of injury., Results: Thirteen animals met our prespecified criteria for exclusion, and data for 59 rats were presented here. Hypothermia was associated with a 63% reduction in infarct size, and pethidine had no significant impact on the efficacy of hypothermia. No effects were observed in neurobehavioral outcome or edema volume across experimental groups., Conclusions: The effects of hypothermia in a model of focal ischemia are not affected by administration of pethidine., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

Aim of the Study: The Chinese herbs of myrrh and frankincense are often combined for treating some inflammatory pain diseases with synergistic therapeutic effects. In this study, we investigated the effects of individual herbal extracts and combined extract on anti-inflammatory and analgesic activities in vivo and analyzed the potential bioactive components from the combination extract by ultra-performance liquid chromatography coupled with mass spectrum (UPLC-MS/MS)., Materials and Methods: The anti-inflammatory activities were investigated by utilizing the paw edema mice induced by formalin and carrageenan. In addition, we determined the levels of PGE(2) and nitrite in the edema paw. The analgesic activity was examined against oxytocin-induced dysmenorrhea in mice. The effects of the administration of dolantin or indomethacin were also studied for references. The components in combination extract (CWE) were analyzed by UPLC-MS/MS., Results: The results showed that myrrh water extract (MWE) and the combined extract (CWE) at the 3.9 g/kg, and 5.2 g/kg showed inhibition of formalin-induced paw edema with inhibition rate of 30.44%, and 23.50%, respectively. The PGE(2) production was inhibited significantly by all samples (P<0.01 or P<0.05). CWE showed stronger suppression on carrageenan-induced mice paw edema at 2 and 3h after administration of drugs. The inhibitory effect of CWE on nitrite production was between that of MWE and water extract of frankincense (FWE) at 5.2 g/kg. The dysmenorrhea mice test showed MWE could remarkably reduce the writhing times (P<0.05) and prolong the latency period, while FWE showed no obvious effects on the writhing times. CWE significantly reduced the writhing times and prolong the latency period (P<0.01)., Conclusion: These results demonstrated MWE, FWE, and CWE exhibited significant anti-inflammatory and analgesic activities. The findings suggest that CWE may be therapeutically more useful for mitigating inflammatory pain than individual herbal extract. In addition, 12 potential active compounds were identified from CWE. These data may support the fact the traditional application of this combined extract in treating various diseases associated with inflammatory pain., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Pethidine, an opioid analgesic is used for pain management. Clomipramine a tricyclic antidepressant primarily used for mood management is also used to treat pain. The objective of this study was to investigate the potentiation of the analgesic effects of sub-threshold dose of pethidine by a tricyclic antidepressant, clomipramine., Methods: The antinociceptive activities of clomipramine and pethidine alone and in combination were investigated in Swiss albino mice using the formalin test. Normal saline was employed as the control. Ten animals were used in each experiment., Results: Pethidine 5mg / kg failed to cause any significant effect while the 6.25, 7.5, 8.75 and 10.0mg /kg showed highly significant antinociceptive effect (p< 0.01) compared to the controls in the late phase of formalin test. Clomipramine 0.5 mg / kg did not show any significant effect while 0.75 mg / kg caused a significant effect (p< 0.05) while 1.00 and 1.25mg /kg caused a very highly significant antinociceptive effect (p< 0.001) in the late phase of formalin test compared to the vehicle treated animals. The combination of pethidine 5mg / kg and clomipramine 0.75 mg / kg caused a highly significant antinociceptive effect (P<0.01) in the late phase of formalin test., Conclusion: This study demonstrates a marked reduction in the time spent in pain behaviour produced by the combination of low dose pethidine and clomipramine in the late phase of formalin test. The findings demonstrate the potentiation of a narcotic analgesic by a tricyclic antidepressant.

Both pharmacological and nonpharmacological methods are used to control shivering in therapeutic hypothermia. An evidence-based protocol based on the most current research has been developed for the management of shivering during therapeutic hypothermia. Meperidine is the drug of choice and provides the greatest reduction in the shivering threshold. Other effective pharmacological agents recommended for reducing the threshold include dexmedetomidine, midazolam, fentanyl, and magnesium sulfate. In addition, skin counterwarming techniques, such as use of an air-circulating blanket, are effective nonpharmacological methods for reducing shivering when used in conjunction with medication. As a last resort, neuromuscular blocking agents are considered appropriate therapy for management of refractory shivering.

Postanesthesia shivering is an undesirable event that may induce a variety of adverse consequences including patient discomfort, increased oxygen consumption and wound pain. Thus, its pharmacological treatment should be regarded. The purpose of this study was to compare the efficacy of morphine, fentanyl and pethidine for the treatment of postanesthesia shivering. Fifty patients who developed shivering were treated in a randomized double blinded manner with an intravenous bolus dose of 2 or 4 mg morphine, 25 or 50 mg pethidine, and 50 μg fentanyl. Then, they were monitored for 30 minutes and the shivering suppression grade, the time taken to stop shivering, the shivering cessation time, recurrence of shivering and opioid side effects were evaluated. Core body temperature was measured immediately before, and at 15 and 30 minute after administering the drug. The groups did not differ significantly regarding shivering suppression grade, shivering cessation time, and recurrence of shivering. There was a significant difference in the time taken to stop shivering between groups. Following injection of the drugs, the core temperatures increased in the five groups with statistical difference. All opioids were effective in treating postanesthesia shivering in a similar extent.

Objectives: To compare the analgesic and sedative effects of butorphanol and pethidine (meperidine) in dogs., Methods: Twenty-eight female dogs undergoing ovariectomy (20) or ovariohysterectomy (8) were randomly divided into two groups. Pre-anaesthetic medication in group B consisted of 20 μg/kg intramuscular (im) acepromazine and 0·4 mg/kg butorphanol, while group P received 20 μg/kg acepromazine with 5 mg/kg pethidine. The resulting sedation (simple descriptive scale), propofol dose required to induce anaesthesia, several intraoperative cardiorespiratory variables and postoperative pain (Colorado Pain Scoring System) were compared between the two groups. A 0·2 mg/kg meloxicam dose was administered intravenously to all animals at the end of the 4 hours observation period, or earlier if the pain score was more than 13., Results: Sedation scores, propofol induction doses and intraoperative cardiorespiratory variables were not different between groups. Postoperative pain scores were also similar although one dog in group B required rescue analgesia. Five dogs in group P vomited postoperatively., Clinical Significance: Either butorphanol and pethidine, combined with acepromazine, produced reliable sedation and analgesia up to 4 hours after intramuscular injection in dogs., (© 2011 British Small Animal Veterinary Association.)

To compare the effects of neurotropic and musculotropic spasmolytic drugs in isolated swine uterus specimens, 80 swine uteri were perfused using an established model for preserving a viable organ that responds to oxytocic hormones and spasmolytic drugs. An intrauterine catheter was used to record pressure changes. Following initiation of rhythmic uterine contractions and recording of spontaneous rhythmic contractions, spasmolytic drugs (butylscopolamine, atropine, denaverine, morphine, metamizole, pethidine and celandine) were administered at various concentrations. The musculotropic relaxant denaverine in particular showed significant results (P ≤ 0.05) for all dosages and parameters investigated. In terms of muscle physiology, musculotropic agents (denaverine and celandine) have clear advantages in comparison with neurotropic (butylscopolamine and atropine) or musculoneurotropic (morphine, metamizole and pethidine) spasmolytic drugs for inhibiting contractions. Experiments with pethidine (Dolantin) also showed promising results; with celandine (Paverysat), an initial increase in contractions was observed that may suggest ways of promoting rapid directed sperm transport. Denaverine and pethidine in particular may in the future be able to play an important role in improving the pregnancy rate after IVF., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The bispectral index (BIS) monitor records electroencephalogram waveforms and provides an objective measure of the hypnotic effect of a sedative drug on brain activity. The aim of this pilot study was to use the BIS monitor to evaluate the depth of procedural sedation in pediatric dental patients and to assess if the BIS monitor readings correlate with a validated pediatric sedation scale, the University of Michigan Sedation Scale (UMSS), in determining the level of sedation in these patients. Thirty-five pediatric dental patients requiring sedation were studied prospectively. A baseline BIS reading was obtained and during the procedure an independent observer recorded the BIS every 5 minutes. The operator, who was blinded to the BIS results, determined the UMSS scale at the same 5-minute interval. The patients were monitored postoperatively for 1 hour. There was a significant but moderate correlation between BIS values and UMSS scores (Spearman's rank correlation r  =  -0.574, P < .0001). Percentage of agreement and kappa coefficient using all the observations were also calculated. The percentage of agreement was 37.8%, the kappa coefficient was 0.18 (P < .0001), and the weighted kappa coefficient 0.26 (P < .0001). A lack of correlation was noted between the deeper levels of UMSS sedation scores and BIS values. This study demonstrated a significant correlation between BIS values and the UMSS score in pediatric dental patients undergoing mild to moderate sedation. Based on our results, it appears that the BIS monitor may be useful during mild or moderate sedations to establish the level of sedation objectively without the need to stimulate the patient.

Parenteral opioids for pain relief during labor have been the subject of research for many decades. Commonly used systemic opioids provide limited pain relief during labor yet are used extensively for managing labor pain. These opioids share similar pharmacologic profiles but differ in potency, pharmacokinetics, and side effects. This article reviews the pharmacokinetics, pharmacodynamics, and clinical research related to the commonly used systemic labor pain analgesics morphine, meperidine, fentanyl, remifentanil, butorphanol, and nalbuphine., (© 2011 by the American College of Nurse-Midwives.)

Aim of the Study: This present study was carried out to evaluate the anti-inflammatory and analgesic effects of 85% ethanol extract (EE) of Commiphora myrrha and its different fractions partitioned with petroleum ether extract (EPE), ethyl acetate extract (EEA), n-butanol extract (EBu), and the water extract (ECY). Moreover, the chemical constituents in EPE were analyzed and identified by UPLC-QTOF/MS/MS., Materials and Methods: The anti-inflammatory activities were investigated by utilizing the paw edema mice induced by formalin. In addition, we determined the levels of PGE(2) in the edema paw. While the analgesic activity was examined against thermally and chemically induced nociceptive pain in mice, using the acetic acid and hot-plate test methods. The effects of the administration of dolantin or indomethacin were also studied for references. The components in EPE were analyzed by the ultra-performance liquid chromatography coupled with mass spectrum., Results: In the anti-inflammatory test, EE inhibited the development of paw swelling induced by formalin significantly. The pharmacological activities of the petroleum ether fraction (EPE) were stronger than the EE extract and other fractions at the dose of 100mg/kg, and furthermore significantly decreased the levels of inflammatory factor PGE(2) in the edema paw tissue at the fourth hour after formalin injection. It has been also shown that the ethanol extract (EE) significantly reduced acetic acid-induced writhing response in mice at the dose of 200mg/kg, and 100mg/kg. The petroleum ether fraction (EPE) showed significant analgesic activity in the model at the dose of 100mg/kg (p<0.01), and the ethyl acetate fraction (EEA) exhibited less analgesic activity (p<0.05). All test samples showed no significant analgesic activity on the hot plate pain threshold in mice. The UPLC-MS/MS chromatogram analysis of EPE stated that EPE contains the ingredients of sesquiterpenes, diterpenes, and diterpenic acids. Moreover, seven main compounds were identified., Conclusion: These data demonstrated that the EE and EPE posses analgesic and anti-inflammatory activities and may support the fact the traditional application of this herb in treating various diseases associated with inflammatory pain., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: Shivering causes various adverse disturbances and interferes with monitoring. The optimal dose of intrathecal meperidine to prevent shivering without producing other side-effects remains unknown. This prospective randomised double-blinded study was conducted to compare the antishivering effects of two different doses of intrathecal meperidine., Methods: Seventy two parturients, scheduled for elective caesarean section under spinal anaesthesia, were enrolled in three different groups. Spinal anaesthesia consisted of bupivacaine 0.5% (10 mg) for the control group (M0), and the same dose of bupivacaine with meperidine 12.5 or 25 mg for the experimental groups (M1, M2). Blood pressure, heart rate, skin and core temperatures, sensory level, capnometry, pulse oximetry, Apgar scores, shivering intensity and intrathecal opioid-related side-effects were evaluated and recorded by a blinded observer. Data were analysed using analysis of variance, χ² test, Kruskal-Wallis H-test and Mann-Whitney U-test. A P value less than 0.05 was considered to be significant., Results: Shivering was more intense in group M0 than in groups M1 and M2 with P values of 0.003 and less than 0.001, respectively. The intensity of shivering was comparable in groups M1 and M2. As regards the incidence of significant shivering, it was found to be highest in M0 (4/24 ≈16.7%) in comparison with M1 (0/24) and M2 (0/24) (P = 0.03). Nausea and vomiting occurred more frequently with higher doses of meperidine (P < 0.001 and P = 0.003, respectively). Other complications were comparable., Conclusion: The use of intrathecal meperidine for caesarean section during spinal anaesthesia for the prevention of shivering cannot be recommended as its use is associated with increased incidence of nausea and vomiting.

A novel conotoxin lt14a containing 13 amino acid residues with an amidated C-terminus derived from Conus litteratus, belongs to C-C-C-C cysteine pattern. As the smallest peptide of conotoxin framework 14, lt14a could inhibit nicotinic acetylcholine receptor and suppress pain. To elucidate structure-function relationship, we determine the solution structure by NMR and find that lt14a comprises a short duple β-strand region and β-turn motif. An analog [K7A]-lt14a of Ala substitution for Lys in position 7 is designed. Interestingly, [K7A]-lt14a exhibits higher activity than lt14a as long-lasting analgesic in the hotplate pain model in mice. Additionally, MTT assay reveals that the two peptides have low toxicity to human cells. The studies suggest that positively charged residue may not be involved in the blocking mechanism. However, due to the Ala substitution, hydrophobic residues' patch expansion strengthens the binding ability. A hypothesis is given that in conotoxin lt14a, hydrophobic residues rather than charged residues play a key role during target binding., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The present study was undertaken to evaluate the antinociceptive effects of an ayurvedic polyherbal formulation in rats and mice employing the tail immersion test and acetic acid-induced writhing test, respectively., Materials and Methods: With the tail immersion method, rats received two different doses (270 and 405 mg/kg BW, p.o.) of a formulation, pethidine (5.4 mg/kg BW, p.o.) as a reference standard and the combination of the higher dose of the formulation with naloxone (2 mg/kg, i.p.), an opioid receptor antagonist, and caffeine (16 mg/kg, i.p.), used as an adenosine receptor antagonist. In the acetic acid-induced writhing test, mice received two different doses (390 and 585 mg/kg, BW, p.o.) of formulation, diclofenac sodium (15 mg/kg, BW, p.o.) as a reference standard and the combination of the higher dose of the polyherbal formulation with ondansetron (0.5 mg/kg, i.p.), a serotonin receptor antagonist., Results: The polyherbal formulation (405 mg/kg) exhibited a significant (p < 0.01) antinociceptive effect using the tail immersion method. In the acetic acid-induced writhing test, the formulation showed significant (p < 0.01) dose-dependent activity. The antinociceptive effect of the polyherbal formulation apparently involved an opiate-like mechanism, since its antinociceptive action was attenuated by naloxone pretreatment. In addition, antinociceptive activity was attenuated by caffeine and reversed by ondansetron pretreatment., Conclusion: Our data suggest that the polyherbal formulation possessed centrally and peripherally mediated antinociceptive properties. The activity could be mediated through opioid, adenosine, and serotonin receptors and via inhibition of cyclo-oxygenase- and/or lipoxygenase-dependent pathways., (Copyright © 2010 S. Karger AG, Basel.)

A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (K(i) values <2nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT >1500)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Synthesis of glucosylceramide via glucosylceramide synthase (GCS) is a crucial event in higher eukaryotes, both for the production of complex glycosphingolipids and for regulating cellular levels of ceramide, a potent antiproliferative second messenger. In this study, we explored the dependence of the early branching eukaryote Giardia lamblia on GCS activity. Biochemical analyses revealed that the parasite has a GCS located in endoplasmic reticulum (ER) membranes that is active in proliferating and encysting trophozoites. Pharmacological inhibition of GCS induced aberrant cell division, characterized by arrest of cytokinesis, incomplete cleavage furrow formation, and consequent block of replication. Importantly, we showed that increased ceramide levels were responsible for the cytokinesis arrest. In addition, GCS inhibition resulted in prominent ultrastructural abnormalities, including accumulation of cytosolic vesicles, enlarged lysosomes, and clathrin disorganization. Moreover, anterograde trafficking of the encystations-specific protein CWP1 was severely compromised and resulted in inhibition of stage differentiation. Our results reveal novel aspects of lipid metabolism in G. lamblia and specifically highlight the vital role of GCS in regulating cell cycle progression, membrane trafficking events, and stage differentiation in this parasite. In addition, we identified ceramide as a potent bioactive molecule, underscoring the universal conservation of ceramide signaling in eukaryotes.