beta-Lipotropin as a prohormone for the morphinomimetic peptides endorphins and enkephalins.
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The hypophysial homomeric peptide beta-lipotropin (beta-LPH-[1-91]) has no morphinomomimetic activity in a bioassay (myenteric plexus-longitudinal muscle of the guinea pig's ileum) or binding assays with stereospecific opiate-receptors of rat brain synaptosome preparations. Incubating beta-LPH-[1-91] at neutral pH with the supernatant aqueous extracts of rat brain generates (fragments of beta-LPH with) morphinomimetic activity in the same assay systems. These results are related to the recently recognized structural relationships between beta-LPH, the newly isolated peptides met-enkephalin (beta-LPH-[61-65]) and alpha-endorphin (beta-LPH-[61-76]) and also to the biologically active fragments of analogs: beta-LPH-[61-64], beta-LPH-[61-65[-NH2, (Met(O)65)-BETA-LPH-[61-65], beta-LPH-[61-69], and beta-LPH-[61-69]. Enzymatic biogenesis of these morphinomimetic peptides would preclude localizing them as such in cellular or subcellular elements with currently available methodology. (+info)
Elimination of the interferences by keto-opiates in the GC-MS analysis of 6-monoacetylmorphine.
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A simple procedure to eliminate the interference from keto-opiates in the analysis of 6-monoacetylmorphine (6-MAM) by gas chromatography-mass spectrometry is described. The pretreatment of urine samples with sodium bisulfite followed by solid-phase extraction results in the elimination of the bisulfite addition products formed from the reaction of the bisulfite ions with the carbonyl carbon of the keto-opiates. This simple procedure results in the accurate quantitation of 6-MAM at a concentration of 4 ng/mL in the presence of keto-opiates up to 10,000 ng/mL. (+info)
Preemptive intravenous morphine-6-glucuronide is ineffective for postoperative pain relief.
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BACKGROUND: Morphine-6-glucuronide (M-6-G), a major metabolite of morphine, is reported to be more potent than morphine when administered intrathecally; however, its efficiency remains under debate when administered intravenously. This study was designed to assess the analgesic efficiency of intravenous M-6-G for the treatment of acute postoperative pain. METHODS: After informed consent was obtained, 37 adults (American Society of Anesthesiologists physical status I-II) who were scheduled for elective open knee surgery were enrolled in the study. General anesthesia was induced with thiopental, alfentanil, and vecuronium and was maintained with a mixture of nitrous oxide/isoflurane and bolus doses of alfentanil. At skin closure, patients were randomized into three groups: (1) morphine group (n = 13), which received morphine 0.15 mg/kg; (2) M-6-G group (n = 12), which received M-6-G 0.1 mg/kg; and (3) placebo group (n = 12), which received saline. At the time of extubation, plasma concentration of morphine and M-6-G was measured. Postoperative analgesic efficiency was assessed by the cumulative dose of morphine delivered by patient-controlled analgesia. Opioid-related side effects were also evaluated. RESULTS: No difference was noted in patient characteristics and opioid-related side effects. Morphine requirements (mean +/- SD) during the first 24 h in the M-6-G group (41+/-9 mg) and the placebo group (49+/-8 mg) were significantly greater (P<0.05) compared with the morphine group (29+/-8 mg). CONCLUSION: A single intravenous bolus dose of M-6-G was found to be ineffective in the treatment of acute postoperative pain. This might be related to the low permeability of the blood-brain barrier for M-6-G. (+info)
The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine.
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AIMS: To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c. i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. METHODS: Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. RESULTS: After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l- 1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P = 0. 09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P = 0.03 and P< 0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log-transformed AUC ratio 0.78, 90% CI 0.66-0.93), M6G (0.72, 90% CI 0.63-0.82), or M3G (0.65, 90% CI 0.54-0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. CONCLUSIONS: Although bioequivalence was demonstrated between the s. c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine. (+info)
GCD quantitation of opiates as propionyl derivatives in blood.
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We describe a method using a gas chromatograph with electron ionization detection (GCD) for the simultaneous determination of morphine, codeine, 6-monoacetylmorphine, ethylmorphine, and dihydrocodeine in blood. The method employs propionic anhydride in the presence of triethylamine to propionylate free hydroxyl groups of the opiates in blood. The quantitation is achieved by using GCD with selected ion monitoring of the two most characteristic ions for each analyte. The quantitation limit was 0.01 mg/L and the linearity was 0.01-10 mg/L for dihydrocodeine, ethylmorphine, and 6-monoacetylmorphine. For the other investigated opiates, the quantitation limit was 0.025 mg/L and linearity was 0.025-10 mg/L. The intraday relative standard deviation (RSD) varied from 7.2 to 10% at the 0.5 mg/L level, and the day-to-day RSDs varied from 7.5 to 11% at the 0.85 mg/L level. (+info)
Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers.
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The pharmacodynamics of morphine-6-glucuronide (M-6-G) i.v. were assessed in 12 healthy male volunteers in an open study. After a single bolus dose of M-6-G 5 mg i.v., we measured antinociceptive effects, using electrical and cold pain tests, and plasma concentrations of M-6-G, morphine-3-glucuronide (M-3-G) and morphine. Pain intensities during electrical stimulation (at 30, 60 and 90 min after injection) and ice water immersion (at 60 min) decreased significantly (P < 0.005) compared with baseline. Mean plasma peak concentrations of M-6-G were 139.3 (SD 38.9) ng ml-1, measured at 15 min. Our data demonstrate that M-6-G has significant analgesic activity. (+info)
Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.
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Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction. (+info)
The glucuronidation of morphine by dog liver microsomes: identification of morphine-6-O-glucuronide.
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Canines are used extensively in the pharmaceutical industry for the preclinical screening of novel therapeutics, yet comparatively little is known about the phase 2 metabolism in this species. In humans, morphine is known to undergo extensive metabolism by glucuronidation, and the UDP-glucuronosyltransferase isoform, which catalyzes the formation of morphine-3-O-glucuronide and morphine-6-O-glucuronide is UGT2B7. This study was designed to investigate the glucuronidation of morphine using dog liver microsomes. Liver microsomes from beagle dogs catalyzed the glucuronidation of morphine-3(and 6)-O-glucuronide at rates 4 to 10 times that of rhesus monkey and human liver microsomes. The K(m) of morphine using beagle dog liver microsomes was approximately 270 microM, which is similar to that found for expressed human UGT2B7. The V(max) for morphine, using dog liver microsomes, was 27 nmol/min/mg of protein. Flunitrazepam inhibited the glucuronidation of morphine in dog liver microsomes, and the K(i) was 40 microM, which is similar to human UGT2B7 for other substrates. The effects of detergents were also investigated with dog liver microsomes, and Brij 35 and Brij 58 were found to be the best detergents to use for maximal activation of the dog liver morphine UGT. These studies suggest that dog has a UGT2B isoform similar to human UGT2B7. (+info)