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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: 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.

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.

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: 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.

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.

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.)

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.

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: 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.)

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.

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.)

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.

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.)

Recent literature has demonstrated significant improvements in neurologic outcomes in patients who have received induced hypothermia in the setting of out-of-hospital cardiac arrest. Through multiple metabolic mechanisms, the induction of hypothermia slows the progression and devastation of transient cerebral hypoxia. Despite these benefits, the desired reduction in core temperature is often a challenging venture as the body attempts to maintain homeostasis through the induction of thermoregulatory processes aimed at elevating body temperature. Shivering is an involuntary muscular activity that enhances heat production in an attempt to restore homeostasis. For successful induction and maintenance of induced hypothermia, shivering, as well as other thermoregulatory responses, must be overcome. Several pharmacologic options are available, either used alone or in combination, that safely and effectively prevent or treat shivering after the induction of hypothermia. We conducted a PubMed search (1966-March 2009) to identify all human investigations published in English that discussed pharmacologic mechanisms for the control of shivering. Among these options, clonidine, dexmedetomidine, and meperidine have demonstrated the greatest and most clinically relevant impact on depression of the shivering threshold. More research in this area is needed, however, and the role of the clinical pharmacist in the development and implementation of this therapy needs to be defined.

Objective: To observe the effects of morphine and pethidine on P-glycoprotein (P-gp) expression in mouse brain microvascular endothelial cells and investigate the role of nuclear factor-kappaB (NF-kappaB) signaling pathway in morphine-induced up-expression of P-gp., Methods: The mouse brain microvascular endothelial cell line (b.END3) was subjected to pre-incubation with NF-kappaB inhibitor PDTC (5 micromol/L) for 1 h followed by stimulation with morphine (1 microg/ml) or pethidine (1 microg/ml) for 24 h. The bEnd.3 cells were then collected for Western blotting for P-gp expression., Results: A 24-h morphine stimulation induced an up-expression of P-gp in bEnd.3 cells by almost 200%. Pethidine in similar conditions did not affect P-gp expression in the cells. PDTC, the specific inhibitor of NF-kappaB, inhibited morphine-induced up-expression of P-gp in the cells., Conclusion: Morphine can induce up-expression of endogenous P-gp in mouse brain microvascular endothelial cells. NF-kappaB signaling pathway is involved in the morphine-induced up-expression of P-gp.

Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tail-flick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile., ((c) 2010 Elsevier B.V. All rights reserved.)

Objective: To compare the efficacy and safety of meperidine hydrochloride and valethamate bromide against placebo in shortening the duration of active labor., Method: We randomly assigned 160 nulliparous women with a singleton pregnancy at term who needed induction of labor to one of 3 treatments: 50 mg of meperidine (n=53), 16 mg of valethamate bromide (n=53), or a normal saline solution as placebo (n=54). All medications were given by slow intravenous infusion. Labor duration was the main outcome measure., Results: The intervals between infusion and complete cervical dilation and between infusion and delivery were significantly reduced (P<0.001 and P<0.01) in the meperidine group (103.0+/-64.5 minutes and 119.8+/-70.2 minutes), in contrast to the placebo group (173.9+/-74.8 minutes and 192.2+/-82.8 minutes). However, differences were not significant between the 2 treatment groups (139.6+/-63.1 minutes and 160.6+/-71.9 minutes), or between the valethamate bromide and the placebo group., Conclusion: Meperidine, but not valethamate bromide, significantly shortened the duration of active labor in nulliparous women with a singleton pregnancy at term.

The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/-) and knockout (-/-) mice. Comparisons were made with SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviours in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT-/- mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT-/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/- mice.

Background: Meperidine has been shown to exhibit a sensory block in peripheral nerves. However, its motor blockade ability is controversial. The aim of this study was to investigate, electroneurographically, the ability of meperidine to inhibit conduction in both sensory and motor fibres in the ulnar nerve., Materials and Methods: The study was conducted in a double-blind, placebo-controlled fashion. Eighteen healthy volunteers were randomized into three groups (Saline, meperidine 1% and meperidine 2%). Three millilitre of the study solution was administered to the ulnar nerve perineurally at the level of the wrist by the guidance of a nerve stimulator. Sensory nerve action potential (SNAP) and compound motor action potential (CMAP) amplitudes were recorded. At least a 20% decrease in the initial response amplitude was accepted as a block., Results: The number of individuals with sensory and motor block with saline, meperidine 1% and meperidine 2% were 0/6, 6/6, 6/6 and 0/6, 5/6, 6/6, respectively (P<0.05). The maximum decrease in the median SNAP and CMAP amplitude values were 4.7% and 8.3% with saline; 38.5% and 46.4% with meperidine 1%; and 100% and 97.8% with meperidine 2%, respectively (P<0.05). Median values for the duration of sensory and motor block with meperidine 1% and meperidine 2% were 45, 52.5 and 30, 32.5 min, respectively., Conclusion: Meperidine blocks sensory and motor nerve conduction in a dose-related manner.

The likely effect of oral and subcutaneous meperidine on maximal electroshock seizure (MES) in mice was studied. Convulsive current fifty (CC50) was assessed to be 46m A, an electrical pulse causing seizure in 50% of test animals. Doses of 15, 30, 60, or 120 mg/kg meperidine given orally or subcutaneously increased the convulsion threshold of MES as evidenced by a significant dose-dependent reduction of MES below control value (p < .05). An initial hyperactivity reaction that was worsened by noisy and tactile stimuli and tail erection followed by sedation was observed after s.c. injection of 60 or 120 mg/kg meperidine. No significant difference was found between meperidine-induced reductions of control MES values obtained one and two hours after oral doses; the depressed MES values obtained one hour after oral administration of meperidine were significantly different and more powerful than those obtained two hours after s.c. drug administrations (p < .05). Combining previous literature information with the present results, we conclude that such an effect of meperidine can be attributed to cerebellar stimulation.

The aim of the study was to evaluate and compare the effects of caudal epidural administration of meperidine (MP), lidocaine (LD), and a combination of the two (MPLD) in six mature saddle horses. Horses were randomly assigned to receive three treatments (MP 0.3 mg/kg; LD 0.2 mg/kg; and MPLD: MP 0.3 mg/kg and LD 0.2 mg/kg), with at least 1 week between treatments. Drugs were injected into the epidural space between the first and second coccygeal areas in conscious standing horses. Analgesia, ataxia, sedation, cardiovascular and respiratory effects, and rectal temperature were recorded at different intervals before (baseline) and after administration. Epidural administration of MPLD resulted in a longer duration of analgesia of the tail, perineum, and upper hind limb regions than did administration of MP or LD alone.

Objective: To measure cutaneous electrical nociceptive thresholds in relation to known thermal and mechanical stimulation for nociceptive threshold detection in cats., Study Design: Prospective, blinded, randomized cross-over study with 1-week washout interval., Animals: Eight adult cats [bodyweight 5.1 +/- 1.8 kg (mean + SD)]., Methods: Mechanical nociceptive thresholds were tested using a step-wise manual inflation of a modified blood pressure bladder attached to the cat's thoracic limb. Thermal nociceptive thresholds were measured by increasing the temperature of a probe placed on the thorax. The electrical nociceptive threshold was tested using an escalating current from a constant current generator passed between electrodes placed on the thoracic region. A positive response (threshold) was recorded when cats displayed any or all of the following behaviors: leg shake, head turn, avoidance, or vocalization. Four baseline readings were performed before intramuscular injection of meperidine (5 mg kg(-1)) or an equal volume of saline. Threshold recordings with each modality were made at 15, 30, 45, 60, 90, and 120 minutes post-injection. Data were analyzed using ANOVA and paired t-tests (significance at p < 0.05)., Results: There were no significant changes in thermal, mechanical, or electrical thresholds after saline. Thermal thresholds increased at 15-60 minutes (p < 0.01) and mechanical threshold increased at 30 and 45 minutes after meperidine (p < 0.05). Maximum thermal threshold was +4.1 +/- 0.3 degrees C above baseline at 15 minutes while maximum mechanical threshold was 296 +/- 265 mmHg above baseline at 30 minutes after meperidine. Electrical thresholds following meperidine were not significantly different than baseline (p > 0.05). Thermal and electrical thresholds after meperidine were significantly higher than saline at 30 and 45 minutes (p < 0.05), and at 120 minutes (p < 0.05), respectively. Mechanical thresholds were significantly higher than saline treatment at 30 minutes (p

Background: Meperidine proved to be more effective in treatment of shivering than equianalgesic doses of other opioids, especially pure mu-agonists. Further, meperidine has well known nonopioid actions including agonistic effects at alpha2-adrenoceptors in vitro. Accordingly, the authors investigated nonopioid receptor-mediated effects of meperidine on thermoregulation using a mice model of nonshivering thermogenesis. To differentiate conceivable alpha2-adrenoceptor subtype specific interactions the authors analyzed wild-type mice and knock-out mice with deletion of the alpha2A-, alpha2B-, or alpha2C-adrenoceptor., Methods: Ten mice per group (n = 60) were injected with saline, meperidine (20 mg/kg), saline plus naloxone (125 microg/kg), meperidine plus naloxone, fentanyl (50 microg/kg) plus naloxone, or meperidine plus atipamezole (2 mg/kg) intraperitoneally. Each mouse was subjected to the six different treatments. Then they were positioned into a plexiglas chamber where rectal temperature and mixed expired carbon dioxide were measured while whole body cooling was performed. Maximum response intensity and thermoregulatory threshold temperature of nonshivering thermogenesis were analyzed., Results: Meperidine decreased the thermoregulatory threshold temperature in wild-type mice and alpha2B- and alpha2C-adrenoceptor knock-out mice. This effect ended after injection of the alpha2-adrenoceptor antagonist atipamezole. In wild-type and alpha2B-adrenoceptor knock-out mice, the decrease of thermoregulatory threshold was not reversible by administration of the opioid receptor antagonist naloxone. In contrast, in alpha2A-adrenoceptor knock-out mice, no decline of thermoregulatory threshold following meperidine injection was detectable. Maximum response intensity of nonshivering thermogenesis was comparable in all groups., Conclusions: The authors' results suggest a major role of alpha2-adrenoceptors, especially the alpha2A subtype, in the mediation of thermoregulatory effects caused by meperidine in mice.

Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-glycoprotein (P-gp), suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of opioids. Addition of a 3-OH to meperidine and the ketone analog of meperidine yielding bemidone and ketobemidone, respectively, significantly increased P-gp substrate affinity. The results of this study have implications in the development of novel analgesics to be utilized as tools to study the contribution of P-gp on the development of central tolerance to opioids.

A series of N-substituted-4-cyano-4-phenylpiperidine analogs were synthesized and evaluated for binding affinity at opioid receptors and showed no affinity. The series similarity to previously reported sigma ligands prompted analysis at sigma receptors to determine the SAR for affinity at sigma receptors. Within the N-substituent series the saturated analogs showed increased affinity at both sigma receptors. Optimal chain length in the N-arylalkyl series for sigma(1) and sigma(2) receptors proved to be N-propylphenyl; extension to a four carbon chain dramatically decreased affinity at both receptors. Substituents in the 4-position affect only sigma(1) affinity; no change in affinity at sigma(2) was shown. The N-isobutyl, N-phenylpropyl, and N-benzyl analogs are worth pursuing due to their good affinity and selectivity at the sigma(1) receptor, whereas the N-benzyl analog exhibits the greatest selectivity for sigma(1).

Unlabelled: background & aims: Current practice guidelines strongly recommend differentiation of deep from moderate sedation during endoscopy. Standard methods of sedation monitoring are labor-intense. Bispectral index monitoring (BIS) is widely used during anesthesia, but its benefits during conscious sedation are controversial. Thus, we performed a prospective observational study to assess its ability for detecting deep sedation during endoscopy., Methods: Patients presenting for elective outpatient endoscopy were monitored simultaneously with the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) and BIS. A combination of a narcotic and benzodiazepine was used, with the target being moderate sedation and analgesia. Deep sedation was defined by MOAA/S score of 1-2 and BIS score of

Objective: Intraoperative comfort and patient satisfaction during surgical procedures under regional anaesthesia can be improved with the use of supplemental intravenous sedation. The authors conducted a study to compare two sedation techniques for surgical procedures performed under regional anaesthesia, i.e., midazolam and pethidine combination compared with midazolam and tramadol combination., Methods: Forty adult American Society of Anaesthesiologists (ASA) grade 1-111 patients, aged between 40-65 years undergoing surgery under regional anaesthesia (sub-arachnoid block) were included. The patients were randomly divided into two groups. All patients received standardized premedication, intraoperative monitoring and oxygen therapy. Group A patients received midazolam 0.03 mg/kg followed by pethidine 20 mg intravenously, and group B patients received midazolam 0.03 mg/kg followed by tramadol 20 mg intravenously after the institution of regional anaesthesia. Monitoring included ECG, blood pressure, respiratory rate, oxygen saturation and sedation score. Complications, if any, were recorded. Monitoring was continued during the recovery room stay. All patients were interviewed in the evening and time of ambulation and rating of OR experience was noted., Results: Data analysis showed no significant difference between pethidine and tramadol for all the haemodynamic variables (p = > 0.05). There was also no significant difference in patient's and surgeon's assessment of their experience. Complications and recovery characteristics also did not show any significant difference., Conclusion: Midazolam-tramadol combination may be used as an alternative to midazolam-pethidine combination for sedation during surgical procedures performed under regional anaesthesia.

Objective: To study early hemodynamic changes and duration of postoperative analgesia between two study groups of intrathecal pethidine and bupivacaine heavy in patients undergoing caesarean section., Methodology: Total number of 60 patients of ASA I and II, undergoing caesarean section were enrolled in the study. All the patients were divided into two groups: Pethidine and Bupivacaine heavy. The dose of pethidine for subarachnoid block was 1mg/kg and in Bupivacaine group 2.2 ml of 0.5% bupivacaine heavy was given intrathecally. Heart rate and blood pressure of all the patients were recorded before subarachnoid block. After giving spinal anesthesia, the heart rate and blood pressure were monitored and recorded in different time intervals. The duration of postoperative analgesia in all patients was recorded in postoperative ward. The APGAR Scores of the babies were recorded in 1 and 5 minutes after delivery. The data were statistically compared using independent sample t-test., Conclusion: The hemodynamic parameters (HR & BP) were compared in different time intervals. The difference in heart rate and blood pressure at different time intervals in the two study groups were statistically insignificant as (p > 0.05). The total duration of postoperative analgesia in patients receiving sole intrathecal pethidine was 8 hours and 30 minutes. Where as, in Bupivacaine group the duration was 2 hrs and 36 minutes. This has been found statistically significant (p<0.05).

P-Glycoprotein (P-gp) is an efflux transporter which is up-regulated at the blood-brain barrier in both morphine- and oxycodone-tolerant rats. Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-gp, suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of compounds, and show that a meperidine analog of greater potency, N-phenylbutyl-N-normeperidine, has low activity as a P-gp substrate and has the potential to be utilized as a tool to study the contribution of P-gp to the development of central tolerance to opioids.

Introduction: Mild therapeutic hypothermia has been shown to improve outcome for patients after cardiac arrest and may be beneficial for ischaemic stroke and myocardial ischaemia patients. However, in the awake patient, even a small decrease of core temperature provokes vigorous autonomic reactions-vasoconstriction and shivering-which both inhibit efficient core cooling. Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. We tested whether a combination of skin warming and a medium dose of meperidine additively would reduce the shivering threshold to below 34 degrees C without producing significant sedation or respiratory depression., Methods: Eight healthy volunteers participated on four study days: (1) control, (2) skin warming (with forced air and warming mattress), (3) meperidine (target plasma level: 0.9 mug/ml), and (4) skin warming plus meperidine (target plasma level: 0.9 mug/ml). Volunteers were cooled with 4 degrees C cold Ringer lactate infused over a central venous catheter (rate asymptotically equal to 2.4 degrees C/hour core temperature drop). Shivering threshold was identified by an increase of oxygen consumption (+20% of baseline). Sedation was assessed with the Observer's Assessment of Alertness/Sedation scale., Results: Control shivering threshold was 35.5 degrees C +/- 0.2 degrees C. Skin warming reduced the shivering threshold to 34.9 degrees C +/- 0.5 degrees C (p = 0.01). Meperidine reduced the shivering threshold to 34.2 degrees C +/- 0.3 degrees C (p < 0.01). The combination of meperidine and skin warming reduced the shivering threshold to 33.8 degrees C +/- 0.2 degrees C (p < 0.01). There were no synergistic or antagonistic effects of meperidine and skin warming (p = 0.59). Only very mild sedation occurred on meperidine days., Conclusion: A combination of meperidine and skin surface warming reduced the shivering threshold to 33.8 degrees C +/- 0.2 degrees C via an additive interaction and produced only very mild sedation and no respiratory toxicity.

Objective: To determine the effect of meperidine administered prior to anesthesia on the incidence of vomiting before, and gastroesophageal reflux (GER) and regurgitation during, the subsequent period of anesthesia in dogs., Study Design: Randomized, controlled trial., Animals: A total of 60 healthy dogs, 4.3 +/- 2.3 years old, and weighing 35.5 +/- 13.1 kg., Methods: Dogs were admitted to the study if they were healthy, had no history of vomiting, and were scheduled to undergo elective orthopedic surgery. The anesthetic protocol used was standardized to include thiopental and isoflurane in oxygen. Dogs were randomly selected to receive one of the following pre-medications: morphine (0.66 mg kg(-1) IM) with acepromazine (0.044 mg kg(-1) IM), meperidine (8.8 mg kg(-1) IM) with acepromazine (0.044 mg kg(-1) IM) or meperidine alone (8.8 mg kg(-1) IM). A sensor-tipped catheter was placed to measure esophageal pH during anesthesia. Gastro-esophageal reflux was judged to have occurred if there was a decrease in esophageal pH below four or an increase above 7.5., Results: No dogs vomited after the administration of meperidine, but 50% of dogs vomited after the administration of morphine. When compared with morphine, treatment with meperidine alone or combined with acepromazine before anesthesia was associated with a 55% and 27% reduction in absolute risk of developing GER, respectively. Dogs receiving meperidine alone were significantly less sedate than other dogs in the study, and required more thiopental to induce anesthesia. Arterial blood pressure and heart rate were not significantly different between groups at the start of the measurement period. Cutaneous erythema and swelling were evident in four dogs receiving meperidine., Conclusions and Clinical Relevance: Administration of meperidine to healthy dogs prior to anesthesia was not associated with vomiting and tended to reduce the occurrence of GER, but produced less sedation when compared with morphine. Meperidine is not a useful addition to the anesthetic protocol if prevention of GER is desired.

Objective: The purpose of this study was to test the hypothesis that meperidine induces a dilator response in the feline pulmonary vascular bed, and to identify receptors involved in the mediation or modulation of these effects., Design: Prospective vehicle controlled study., Setting: University research laboratory., Subjects: Intact chest preparation; adult mongrel cats., Interventions: In separate experiments, the effects of diphenydramine (histamine H(1)-receptor antagonist), glibenclamide (adenosine triphosphate-sensitive K+ channel blocker), L-N(5)-(1-Iminoethyl) ornithine hydrochloride (L-NIO) (nitric oxide synthase inhibitor), naloxone (opioid receptor antagonist), and nimesulide (selective cyclooxygenase-2 inhibitor) were investigated on pulmonary arterial responses to meperidine and other agonists in the feline lung bed., Measurements and Main Results: The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and permanently recorded. Under elevated tone conditions in the isolated left lower lobe vascular bed of the cat, meperidine induced a dose-dependent vasodilator response that was not significantly altered after administration of glibenclamide, L-NIO, and nimesulide. Responses to meperidine were significantly attenuated after the administration of diphenydramine and naloxone., Conclusions: The results suggest that meperidine has potent vasodilator activity in the feline pulmonary vascular bed, and these responses are mediated or modulated, in part, by opioid and histamine receptor-sensitive pathways.

The aim of this study was to compare both the behavioral and physiological effects of 2 drug regimens in children: chloral hydrate (CH), meperidine (M), and hydroxyzine (H) (regimen A) versus midazolam (MZ), M, and H (regimen B). Patients between 24 and 54 months of age were examined by crossover study design. Behavior was analyzed objectively by the North Carolina Behavior Rating System and subjectively through an operator and monitor success scale. Physiological data were recorded every 5 minutes and at critical points throughout the appointment. Sixteen patients completed this study. No significant differences in behavior were noted by the North Carolina Behavior Rating System or the operator and monitor success scale. A quiet or annoyed behavior was observed 93% and 90% of the time for regimen A and regimen B, respectively. Using the operator and monitor success scale, 63% of regimen A and 56% of regimen B sedations were successful. No statistically significant differences were noted in any of the physiological parameters between the 2 regimens. Ten episodes of hemoglobin desaturation were detected with regimen A sedations. There were no differences between the sedative drug regimens CH/M/H and MZ/M/H for behavioral outcomes or physiological parameters.

We performed a prospective, randomised, double blind study to compare the antishivering effect of morphine and pethidine when added to intrathecal hyperbaric bupivacaine during elective Caesarean delivery under combined-spinal epidural anaesthesia. Spinal anaesthesia consisted of either 8-10 mg of 0.5% bupivacaine alone (group B; n = 30) with 0.1 mg morphine (group BM0.1; n = 29), with 0.2 mg morphine (group BM0.2; n = 30), or with 10 mg pethidine (group BPeth10; n = 30). The incidences of shivering were 23.3% (7/30) in group B, 17% (5/29) in group BM0.1, 13.3% (4/30) in group BM0.2 and 3.3% (1/30) in group BPeth10 (p < 0.05). The shivering intensity for each patient was significantly higher in group B than the other groups. In conclusion, intrathecal pethidine added to hyperbaric bupivacaine reduces the incidence and intensity of shivering more than does morphine (0.1 or 0.2 mg).

The structure-activity relationships of 3',4'-dichloro-meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3',4'-dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT=760). Chemical modification of the ester group and N-substitution generally led to compounds with decreased DAT affinity. Only small esters and alkyl groups were tolerated at the 4-position of the meperidine ring system by the DAT. Overall, the meperidine analogues were generally more selective for the SERT than for the DAT.

A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at mu-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K(i) = 0.0072 muM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and mu-opioid receptors (mu/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K(i) = 0.125 muM) and was the most selective ligand for the DAT over mu-opioid receptors (mu/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the mu-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.

Meperidine has potent antishivering properties. The underlying mechanisms are not fully elucidated, but recent investigations suggest that alpha2-adrenoceptors are likely to be involved. We performed the current study to investigate the effects of meperidine on nonshivering thermogenesis in a model of thermoregulation in mice. After injection (0.1 mL/kg intraperitoneally) of saline, meperidine (20 mg/kg), the specific alpha2-adrenoceptor antagonist atipamezole (2 mg/kg), plus saline or atipamezole plus meperidine, respectively, mice were positioned in a Plexiglas chamber. Rectal temperature and mixed expired carbon dioxide were measured after provoking thermoregulatory effects by whole body cooling. Maximum response intensity of nonshivering thermogenesis and the thermoregulatory threshold for nonshivering thermogenesis, which was defined as the temperature at which a sustained increase in expiratory carbon dioxide can be measured, were investigated. Meperidine significantly decreased the threshold of nonshivering thermogenesis (36.6 degrees C +/- 0.7 degrees C) versus saline (37.9 degrees C +/- 0.6 degrees C) and versus atipamezole plus saline (37.8 degrees C +/- 0.4 degrees C; P <0.01). This effect was abolished after administration of meperidine combined with atipamezole (37.7 degrees C +/- 0.6 degrees C; P <0.05). Meperidine did not decrease the maximum intensity of nonshivering thermogenesis. The results suggest a major role of alpha2-adrenoceptors in the inhibition of thermoregulation by meperidine in mice.