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)

1. The effect of experimental inflammation on methadone analgesia was evaluated in rats, by the tail-flick test, after single intravenous (0.35 mg/kg) and subcutaneous (3 mg/kg) doses. 2. After i.v. administration a significant decrease (P < 0.05) in the area under the methadone time-response curve was seen in rats with experimental inflammation, when compared with control. However, no differences in the analgesic response to methadone were detected between control rats and rats with inflammation when the drug was administered by s.c. injection. 3. Plasma mucoprotein levels were significantly increased (P < 0.001) and methadone free fraction was significantly decreased in rats with inflammation (P < 0.05). In addition, after i.v. methadone a decrease in brain uptake in rats with inflammation was detected. A significant correlation between brain uptake index and plasma free fraction was also observed. 4. These results suggest that a decreased immediate response to i.v. methadone may occur in circumstances in which there is an increase in alpha 1 acid glycoprotein, but that this is not likely to be observed when the absorption is not instantaneous.
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PMID:Altered methadone analgesia due to changes in plasma protein binding: role of the route of administration. 759 Jan 18

In a group of mice bearing experimentally induced tumors, the protein binding of mianserin in vitro was measured and compared with a control group. The analgesic effect and the brain uptake of drug was also compared with a control group after an intraperitoneal dose of mianserin. The unbound percentage of mianserin in the plasma of mice with experimental cancer decreased with respect to control animals (5.20 +/- 0.12 vs 6.06 +/- 0.26; p<0.05) and alpha1-acid glycoprotein (AAG) levels, measured as plasma mucoprotein concentrations, were significantly increased (p<0.05). The brain/plasma drug concentration ratio of mianserin decreased in mice with experimental cancer when compared with control mice (1.11 +/- 0.03 vs 1.42 +/- 0.10; p<0.02). In both groups of mice, the mianserin analgesic effect was evaluated by the hot plate test after intraperitoneal drug administration. When the analgesia response-dose curve (0-60 mg/kg) was studied, a significant decrease in the response in mice with experimental cancer versus control mice was observed. These results suggest that resistance to the mianserin analgesic response may occur in animals with cancer disease. This resistance may be associated, in part, with an altered plasma protein binding, but other mechanisms could be involved.
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PMID:Changes in the analgesic effects of mianserin associated with altered plasma protein binding in experimental cancer. 868 Aug 2

The pharmacokinetics and pharmacodynamics of methadone were investigated in control and abstinent rats. Minipumps filled with saline (control group) or saline-morphine (abstinent group) solutions were used to induce physical dependence. Solutions were delivered continuously by minipumps for 6 days. The physical dependence was evaluated 12 h after minipump removal by measuring specific withdrawal signs. Animals from the abstinent group showed clear withdrawal signs such as hostility on handling and weight loss. Plasma and brain disposition and pharmacodynamics of methadone were evaluated after a 0.35 mg/kg i.v. bolus dose administered 12 h after minipump removal. Plasma clearance, distribution clearance, and volume of distribution at steady-state were significantly decreased (P < 0.05) in the abstinent group. Plasma levels of alpha1-acid glycoprotein and plasma protein binding were significantly increased (P < 0.05) in the abstinent group. The estimates of pharmacokinetic parameters based on unbound plasma concentrations did not differ between groups, with the sole exception of the unbound apparent volume of distribution. The access of methadone to the brain was significantly faster (P < 0.05) in the abstinent group, although the extent of distribution in the brain was diminished in comparison with the control group. Analgesia recorded with tail-flick was used as the pharmacodynamic endpoint. Analgesic response and effect compartment concentrations of methadone were related by the sigmoidal Emax model. Estimates of C50 [steady-state plasma concentrations eliciting half of maximum effect (Emax)]] based on unbound concentrations did not differ between groups. On the other hand, the estimate of Emax had decreased by 65% in the abstinent group.
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PMID:Altered plasma and brain disposition and pharmacodynamics of methadone in abstinent rats. 986 69

This study was undertaken: (i) to quantify the effects of labour and epidural analgesia on plasma alpha1-acid glycoprotein concentration, (ii) to examine the effects of changes in plasma alpha1-acid glycoprotein concentration on plasma protein binding and placental transfer of ropivacaine, and (iii) to examine the association between umbilical venous ropivacaine concentration and neurobehavioural function in the neonate. Multiparous patients undergoing induction of labour received a continuous epidural infusion of 0.1% ropivacaine following an epidural bolus. A significant association was demonstrated between maternal plasma alpha1-acid glycoprotein concentration and 1/free fraction of ropivacaine 60 min after starting ropivacaine administration (r(2) = 0.77) but not at delivery. No significant correlation was demonstrable between maternal unbound ropivacaine concentration and either neonatal (cord) ropivacaine concentration or UV/MV (a measure of placental transfer). Thirty minutes after delivery, 9/10 neonates had neurological and adaptive capacity scores < 35, whereas only three infants had scores < 35 at 2 h. All scores exceeded 35 16 h after delivery. No association between mean (SD) umbilical venous ropivacaine concentration [0.09 (0.08) mg x l(-1)] and neurological and adaptive capacity scores was demonstrated.
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PMID:Epidural ropivacaine hydrochloride during labour: protein binding, placental transfer and neonatal outcome. 1135 Mar 25

The pharmacokinetics of ropivacaine were evaluated during long-term continuous epidural analgesia (CEDA) for about 120 h. The total and free plasma concentrations of ropivacaine and the alpha1-acid glycoprotein (AAG) concentration were measured in 12 patients after total knee arthroplasty. The infusion rate was adjusted according to patients' analgesic needs or side effects. The mean (SD) rate of infusion of ropivacaine (Naropin 2 mg ml(-1)) was 14.6 (3.2) mg h(-1) on the day of surgery and was increased after surgery to 15.4 (4.4) mg h(-1) on days 1-5. This was equivalent to an absolute dose of 1786 (553) mg of ropivacaine over the entire infusion period. After an initial increase, the mean free ropivacaine plasma concentration nearly plateaued and than decreased slightly after approximately 70 h. The individual peak free plasma concentration was 0.096 (0.034) microg ml(-1). The highest individual free plasma concentration was 0.16 microg ml(-1). The individual peak total plasma concentration, 4.1 (1.2) microg ml(-1), was achieved after 67.7 (16.5) h, although the AAG concentration increased throughout the observation period. Our data support the safety and efficacy of long-term ropivacaine CEDA.
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PMID:Ropivacaine plasma concentrations during 120-hour epidural infusion. 1173 14

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.
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PMID:Drug interactions with patient-controlled analgesia. 1182 96

Methadone is a basic drug highly bound to alpha1-acid glycoprotein (AGP), a plasma protein that increases in several pathological situations. Our aims were to evaluate the processes (pharmacokinetics-PK and/or pharmacodynamics-PD) associated with changes of methadone analgesia under conditions of increased AGP, and whether these changes are dependent on binding, secondary to a pathology, or directly attributable to AGP. AGP levels, in rats, were increased by two different methods: (a) experimental inflammation with turpentine oil (TP), and (b) by directly infusing the protein (exo-AGP). Both had a corresponding control group. Tail-flick analgesia and PK were evaluated after methadone dose (0.35 mg/kg i.v.). Bicompartmental PK parameters as well as interanimal and assay variabilities were estimated using NONMEM. The relationship between Cp and analgesic effect (PD) was analyzed with WINNONLIN. AGP levels in both pretreated groups (TP and exo-AGP) were significantly increased, and the unbound fraction (fu) was decreased, compared to controls. All PK parameters were lower in the pretreated groups, but in exo-AGP the difference was maintained even when corrected by fu. Paradoxically, also in exo-AGP the analgesic effect was practically nonexistent, although the unbound Cp remained high, possibly associated to a change in the PD. AGP appears responsible for alterations in both PK and PD, beyond protein binding and inflammatory processes.
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PMID:Alpha-1-acid glycoprotein directly affects the pharmacokinetics and the analgesic effect of methadone in the rat beyond protein binding. 1545 46