Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper describes the synthesis, structure-activity relationships (SAR) of mu and kappa opioid binding affinities, and analgesic properties of a series of novel highly selective kappa opioid N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy] acetamide derivatives. Ten compounds, 14, 15, 31-37, and 39 (Tables I and II), show a marked kappa selectivity of greater than 100:1 over mu binding, with high affinity for the kappa opioid receptor (approximately 10(-8) - 10(-9) M). Compound 39, (S,S-trans)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-benzo[b] furanacetamide hydrobromide, has the highest mu/kappa selectivity, 780:1 (kappa Ki = 4.2 nM), reported to date. Four of these compounds, 14, 15, and their S,S-trans enantiomers, 37 and 39, respectively, produce effective analgesia by oral administration, as assayed by a rat-paw pressure test (RPP) (MPE50 = 24, 26, 8.3, and 12 mg/kg, respectively). The R,R-trans isomer, 38, was inactive in binding and RPP. The analgesic effect was reversed by administration of naloxone, confirming these effects are opioid in character. Optimal activity is produced when the basic nitrogen atom is in a pyrrolidine ring, the aryl group is a 10-pi-electron-rich aromatic system, such as 4-benzo[b]thiophene, 4-benzo[b]furan, or 4-chlorophenoxy, and overall lipophilicity lies within the range log P = 3.5-5.0.
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PMID:Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives. 283 3

To examine the effects of postoperative epidural analgesia with local anaesthetics or morphine on the excess nitrogen loss after upper abdominal surgery and to assess the roles of catabolic hormones in the nitrogen loss, urinary excretion of nitrogen and catecholamines and plasma concentrations of cortisol and glucagon were measured in three groups of patients undergoing elective gastrectomy. Group G patients received the operation under general anaesthesia, and their postoperative pain was relieved by intermittent injections of analgesics. Group PE received prolonged epidural analgesia with local anaesthetics during and after surgery. Group EM received epidural analgesia intra-operatively and epidural morphine postoperatively. Urinary nitrogen excretion during the first three postoperative days was significantly less in the PE and EM groups than in the G group, and the PE group excreted slightly less nitrogen than the EM group. In the G group, urinary excretion of adrenaline increased mainly on the day of operation, and noradrenaline chiefly on postoperative days. These catecholamine responses were almost completely abolished in the PE group, and significantly inhibited in the EM group. Plasma cortisol response was most remarkable shortly after the operation and then decreased in all groups, but was significantly lower in the two epidural groups than in the G group throughout the study. Plasma glucagon increased postoperatively in all groups, and the increase was less pronounced in both epidural groups than in the G group. These results suggested that an elevated sympathetic activity, represented by increased noradrenaline excretion and elicited by painful nociceptive and sympathetic nervous afferents, is responsible for the postoperative nitrogen loss which is mediated by glucagon and cortisol.
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PMID:Effects of epidural administration of local anaesthetics or morphine on postoperative nitrogen loss and catabolic hormones. 359 44

Postoperative pulmonary function was studied in 16 patients undergoing total hip or knee arthroplasty. Their mean age was 65 years. Half of them received spinal analgesia (22.5 mg bupivacaine + 0.3 mg morphine) and the other half underwent general anaesthesia with halothane-nitrous oxide. Four hours postoperatively, the forced expirogram was maintained in the spinal analgesia group, compared with preanaesthesia measurements. Functional residual capacity (FRC) measured by multiple breath nitrogen washout was reduced by 0.51, as was closing capacity (CC) measured by the bolus technique. The gas distribution index (nitrogen washout delay) was unaltered. The alveolar-arterial oxygen tension difference (PA-ao2) was not significantly altered, but arterial oxygen tension (Pao2) was reduced by 1.7 kPa, and arterial carbon dioxide tension (PaCo2) was increased. No respiratory measurements could be made in the general anaesthesia group 4 h postoperatively, but arterial blood gases were unaltered compared with preanaesthesia values. Eighteen hours postoperatively, forced vital capacity (FVC) was reduced in the spinal analgesia group, FRC and CC remained diminished and the gas distribution index was increased, indicating less efficient gas mixing. Simultaneously, PA-ao2 was increased, and Pao2 remained reduced despite increased alveolar ventilation (lowered PaCo2). In the general anaesthesia group FVC, FRC and CC were also reduced, but the gas distribution index remained at the awake level and blood gases were unaltered. It is suggested that the slight hypoventilation in the spinal analgesia group early after surgery may have contributed to impaired gas distribution and ventilation-perfusion matching later postoperatively.
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PMID:Effect of anaesthesia on respiratory function after major lower extremity surgery. A comparison between bupivacaine spinal analgesia with low-dose morphine and general anaesthesia. 397 22

Twenty patients undergoing major abdominal surgery were allocated randomly to receive either general anaesthesia with low-dose fentanyl plus intermittent systemic morphine for postoperative pain or the same general anaesthetic plus extradural analgesia during and following surgery (local anaesthetics from before skin incision until 24 h after skin incision plus extradural morphine 4 mg every 12 h from 3 h to 72 h after skin incision). Postoperative pain scores were lower (P less than 0.05) in the group receiving extradural analgesia, but this regimen failed to prevent the increase in the urinary excretion of cortisol, adrenaline, noradrenaline and nitrogen both on separate days and on cumulative measurements over 4 days. Pain scores did not correlate to urinary excretion of the various endocrine-metabolic indices either on separate days or over the cumulative 4-day period. It is concluded that the relief of pain per se has no major influence on the catabolic response to abdominal surgery.
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PMID:Effects of the extradural administration of local anaesthetic agents and morphine on the urinary excretion of cortisol, catecholamines and nitrogen following abdominal surgery. 398 68

Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a nonenkephalin peptide, is an opioid agonist highly selective for mu opiate receptors. Chemical modification of Tyr-Pro-Phe-Pro-NH2 was carried out by substituting structurally related amino acids at residues 2, 3 and 4. The morphiceptin analogs synthesized were then examined for receptor binding activities using 125I-labeled FK 33,824 (Tyr-D-Ala-Gly-NMePhe-Met(O)-ol) as the mu-ligand and 125I-labeled D-Ala2,D-Leu5-enkephalin as the delta-ligand, and for inhibitory activities on electrically evoked smooth muscle contraction of mouse vas deferens and isolated myenteric plexus-longitudinal muscle strips of guinea-pig ileum. All of these analogs showed virtually no activity at delta opiate receptor binding sites. Methylation of the nitrogen atom of phenylalanine and the substitution at the C-terminal of L-proline by D-proline produced potent mu-agonists, the prototype analog being Tyr-Pro-NMePhe-D-Pro-NH2 (PL017). The IC50 values of morphiceptin and its analogs for mu receptor binding were correlated to the ED50 values in the guinea-pig ileum assay, suggesting that the ileum effects were mediated by mu receptor interactions. A similar correlation between mu receptor binding activity and the ED50 values in the mouse vas deferens assay suggested that morphiceptin and its analogs also acted on mu receptors in this tissue. This idea is supported by the observation that naloxone has a high pA2 value of 8.71 against PL017 in mouse vas deferens. In in vivo studies, PL017 administered centrally into the rostral portion of the 4th ventricle produced long-lasting, naloxone-reversible analgesia in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potent morphiceptin analogs: structure activity relationships and morphine-like activities. 631 1

Anaesthesia was induced in 65 parturients undergoing elective caesarean section with thiopentone 3,5 mg/kg and suxamethonium 1,5 mg/kg intravenously. For anaesthetic maintenance patients were randomly divided into two groups. Patients in group A were ventilated with 50% nitrous oxide in oxygen, supplemented with 0,6-0,8% enflurane and 50 mg pethidine given intravenously after delivery. Group B patients were ventilated with 50% oxygen in nitrogen and received a continuous intravenous infusion of ketamine (70 micrograms/kg/min), with 5 mg diazepam intravenously following delivery. All patients received intravenous alcuronium 0,2 mg/kg. Inspired oxygen concentration (0,5) and end-tidal carbon dioxide tensions (4,0-5,0 kPa), were standardized. Despite a high incidence of predelivery hypotension in group A but not in group B, the fetal acid-base status, materno-placento-fetal exchange and immediate clinical state of the neonates were comparable. Neonatal neurobehavioural assessment scores assessed 2-4 hours after birth favoured the inhalation technique, but this difference disappeared at 24 hours. A higher incidence of factual recall in group B (14,3% v. 7,4%), frequently painful (10,7% v. 0%), the reporting of unpleasant dreams and a lack of significant postoperative analgesia makes the ketamine infusion technique unsatisfactory.
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PMID:Total intravenous anaesthesia using low-dose ketamine infusion for caesarean section. A comparison with a standard inhalation anaesthetic technique. 642 Sep 4

This study was undertaken to measure the blood concentrations of bupivacaine associated with a single loading dose followed by continuous epidural infusion for the management of the pain of labor and delivery with special reference to the potential for accumulation and toxicity. Four-milliliter venous blood samples were obtained every 15 min following the loading dose until delivery. If inadequate analgesia was observed just prior to delivery, an additional dose of bupivacaine was administered. Bupivacaine concentrations were measured using a double extraction technique followed by gas chromatographic analysis using a nitrogen-specific detector. Clearance, volume of distribution, and rate of absorption were estimated from the blood concentration time data and were 43.39 +/- 11.46 L/h, 67.56 +/- 17.66 L, and 8.97 +/- 3.69 h-1, respectively. Peak serum bupivacaine concentrations were 0.68 +/- 0.14 microgram/ml and occurred 0.58 +/- 0.25 h following administration of the loading dose. The duration of bupivacaine infusion was 3.42 +/- 0.80 h. Serum bupivacaine concentrations at delivery or just prior to administration of a supplemental delivery dose were significantly lower than the peak concentration in all patients (p less than 0.001). Fetal-to-maternal serum concentration ratios were found to be 0.44 +/- 0.16 for the six patients requiring a supplemental delivery dose and 0.44 +/- 0.13 for the six patients receiving bupivacaine only by infusion. The data reported here illustrate that epidural analgesia for labor and delivery achieved using a single 50-mg loading dose followed by a continuous infusion of 12.5 mg/h of bupivacaine will not result in maternal or fetal accumulation or toxicity.
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PMID:Serum bupivacaine concentrations in term parturients following continuous epidural analgesia for labor and delivery. 651 1

The area of ectopic epithelium and transformations zone of the uterine cervix was treated cryosurgically by liquid nitrogen in 252 patients. The influence of deep freeze lasted four minutes. Neither analgesia nor anaesthesia was necessary. After a single cryosurgery cure rate was 92 per cent, after a second application 98 per cent. Cryotherapy can be performed ambulatorily and is nowadays to be regarded as method of choice to restore benign cervical lesions.
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PMID:[Ambulatory cryosurgical restoration of benign cervical lesions]. 674 39

During five alternating three-week periods either methoxyflurane-nitrous oxide or nitrous oxide alone was used for obstetrical analgesia. Delivery ward personnel were followed by venous blood samples once a week. Analyses of blood urea nitrogen, serum uric acid, SGOT and SGPT showed significantly elevated levels three days after exposure to methoxyflurane. This study demonstrates the importance of the scavenging of anesthetic gases to reduce the exposure of personnel to inhalational agents used in delivery suites. Since definite alterations in the indices of both hepatic and renal functions were recognized in obstetrical personnel following exposure, a re-evaluation of the use of methoxyflurane for obstetrical analgesia is suggested.
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PMID:Hepatic and renal effects of low concentrations of methoxyflurane in exposed delivery ward personnel. 721 59

To determine whether the type of peri-operative analgesic regimen affects the metabolic response during and after surgery, we studied 19 women undergoing abdominal hysterectomy under propofol anaesthesia. Patients were randomized to receive either continuous intravenous opioid or a bupivacaine-opioid mixture through a lumbar epidural catheter. Total body oxygen consumption and carbon dioxide excretion, blood glucose and haemodynamic variables were determined up to 24 h after surgery. No differences in any metabolic or haemodynamic variables were noted during surgery. In the post-operative period, the increase in oxygen consumption up to pre-operative values, the urinary nitrogen excretion and the changes in acute phase proteins were similar in both treatment groups. In contrast, the respiratory quotient was significantly higher in the lumbar epidural group than in the intravenous opioid group, 0.87 (SD 0.04) vs 0.77 (SD 0.06) (P < 0.05) and the hyperglycaemic response was more delayed in the epidural group. These data suggest that prolonged sympathetic blockade associated with epidural analgesia might contribute to better preservation of glucose homeostasis in the perioperative period.
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PMID:Metabolic response to lower abdominal surgery: analgesia by epidural blockade compared with intravenous opiate infusion. 751 54


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