RESUMEN
UNLABELLED: Postoperative pain control after cesarean delivery under spinal anesthesia is effectively obtained with morphine 0.1-0.3 mg intrathecally, although there may be dose-dependent side effects. We evaluated the quality of analgesia and the incidence of side effects with smaller doses of intrathecal morphine combined with intramuscular (i.m.) diclofenac. One hundred-twenty pregnant patients were allocated into six groups, which received the following treatments: Groups 1, 3, and 5 received 0.1, 0.05, and 0.025 mg of intrathecal morphine, respectively, plus 75 mg of i.m. diclofenac every 8 h; Groups 2, 4, and 6 received 0.1, 0.05, and 0.025 mg of intrathecal morphine, respectively, plus i.m. diclofenac on demand. Spinal anesthesia was performed with 15 mg of 0.5% hyperbaric bupivacaine. Pain scores and side effects were evaluated hourly for the first 24 h. Groups 1 and 2 had lower pain scores than Groups 3, 4, 5, and 6. However, only patients in Groups 2, 4, and 6 requested additional analgesics. Severe pruritus was more frequent in Groups 1 and 2. No patient experienced respiratory depression. We conclude that there is no advantage in using doses larger than 0.025 mg of intrathecal morphine if they are combined with systemic diclofenac. IMPLICATIONS: A multimodal approach to pain control may provide good quality analgesia while reducing drug-related side effects. In this study, a very small dose of intrathecal morphine, in association with intramuscular diclofenac, proved effective for controlling pain after cesarean delivery, with a low incidence of morphine-induced pruritus.
Asunto(s)
Cesárea , Diclofenaco/administración & dosificación , Morfina/administración & dosificación , Femenino , Humanos , Inyecciones Espinales , Morfina/efectos adversos , Náusea/inducido químicamente , Dolor Postoperatorio , Embarazo , Prurito/inducido químicamenteRESUMEN
Polychlorinated biphenyls (PCBs) may undergo cytochrome P-450-catalyzed hydroxylations to form chlorinated dihydroxybiphenyl metabolites. When the hydroxyl groups are ortho or para to each other, oxidation to a quinone may be catalyzed by peroxidases present within the cell. In order to study the reactivity of PCB-derived quinones, selected chlorophenyl 1,2- and 1,4-benzoquinones were synthesized and characterized, including their reduction potentials against a saturated calomel electrode. Two quinones, 4-(4'-chlorophenyl)-1,2-, and 4-(3',4'-dichlorophenyl)-1,2-benzoquinone, were obtained via the oxidation of the corresponding dihydroxybiphenyls with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Six 1,4-benzoquinones were synthesized via the Meerwein arylation: 2-(2'-chlorophenyl)-1,4-, 2-(3'-chlorophenyl)-1,4-, 2-(4'-chlorophenyl)-1,4-, 2-(2',5'-dichlorophenyl)-1,4-, 2-(3',4'-dichlorophenyl)-1,4-, and 2-(3',5'-dichlorophenyl)-1,4-benzoquinone. As a model study, the rate of reactivity of 2-(4'-chlorophenyl)-1,4-benzoquinone toward the nitrogen nucleophiles glycine, L-arginine, L-histidine- and L-lysine was determined under pseudo-first-order conditions at pH 7.4. The rate constants ranged from 0.45 to 0.75 min-1 M-1. Higher rates were obtained under conditions of higher pH. Two reaction products were identified as the 5- and 6-ring addition products in the ratio of 1:4. In contrast, the reaction of 2-(4'-chlorophenyl)-1,4-benzoquinone with the sulfur nucleophiles glutathione or N-acetyl-L-cysteine was instantaneous. The major product of the reaction of glutathione with 2-(4'-chlorophenyl)-1,4-benzoquinone was also the 6-ring addition product. The hydroquinone thioether could be enzymatically reoxidized to the quinone thioether. Also, the influence of atmospheric oxygen and superoxide dismutase on the rates of the following horseradish peroxidase/H2O2-catalyzed oxidations was investigated: 3,4-dichloro-2',5'-dihydroxybiphenyl to 2-(3',4'-dichlorophenyl)-1,4-benzoquinone and 3,4-dichloro-3',4'-dihydroxybiphenyl to 4-(3',4'-dichlorophenyl)-1,2-benzoquinone. While the presence or absence of atmospheric oxygen did not alter the rates of the oxidation reactions, the presence of superoxide dismutase significantly increased the rates of both oxidation reactions, having the greater effect on the oxidation of the 1,4-hydroquinone. These data show that PCB-derived quinones react with both nitrogen and sulfur nucleophiles of the cell and may explain, in part, the toxic effects of individual PCBs and PCB formulations, such as glutathione depletion, oxidative stress, and cell death.
Asunto(s)
Aminoácidos/química , Bifenilos Policlorados/química , Quinonas/síntesis química , Superóxido Dismutasa/química , Aminoácidos/metabolismo , Aminoácidos Sulfúricos/química , Aminoácidos Sulfúricos/metabolismo , Benzoquinonas/síntesis química , Benzoquinonas/metabolismo , Compuestos de Bifenilo/síntesis química , Catálisis , Peroxidasa de Rábano Silvestre/metabolismo , Cinética , Espectrometría de Masas/métodos , Modelos Biológicos , Nitrógeno/química , Nitrógeno/metabolismo , Oxidación-Reducción , Bifenilos Policlorados/metabolismo , Quinonas/metabolismo , Espectrofotometría , Superóxido Dismutasa/metabolismoRESUMEN
Polychlorinated biphenyls (PCBs) may be metabolically activated to electrophiles, which bind to proteins and nucleic acids. One activation scheme involves the formation of reactive arene oxide intermediates during cytochrome P450-catalyzed hydroxylation. We propose a second activation pathway whereby PCB catechol and hydroquinone metabolites may be oxidized to reactive semiquinones and/or quinones. By employing 4-monochlorobiphenyl (4-MCB) as a model substrate and liver microsomes from rats treated with phenobarbital and 3-methyl-cholanthrene, five monol and three diol metabolites were identified. The major metabolite was 4-chloro-4'-monohydroxybiphenyl, followed by, in decreasing order, 4-chloro-3',4'-dihydroxybiphenyl, unknown B (a monol), 4-chloro-2',3'-dihydroxybiphenyl, 4-chloro-3'-hydroxybiphenyl, 4-chloro-2',5'-dihydroxybiphenyl, unknown A (a monol), and 4-chloro-2'-monohydroxybiphenyl. A trace of a dihydrodiol was detected by GC/MS. To elucidate the source of the diols, 4-MCB and the synthetic monol metabolites 4-chloro-2'-/-3'-/-4'-monohydroxybiphenyls were each employed as substrates in incubations with microsomes from rats treated with phenobarbital, 3-methylcholanthrene, or both inducers. The three diol metabolites were all produced from 4-MCB in incubations with microsomes from 3-methylcholanthrene-treated rats, but incubations with microsomes from phenobarbital-treated rats did not yield detectable amounts of 4-chloro-2',3'-dihydroxybiphenyl. 4-Chloro-2',3'-dihydroxybiphenyl was only found as a product of 4-chloro-2'-monohydroxybiphenyl. The 4-chloro-2',5'-dihydroxybiphenyl was found in extracts of incubations with 4-chloro-2'- and -3'-monohydroxybiphenyls, while the 4-chloro-3',4'-dihydroxybiphenyl was the only product found from 4-chloro-3'- and -4'-monohydroxybiphenyls. No other chlorinated diols were detected by GC/MS. These data suggest that the major route of biosynthesis of the diols was via a second hydroxylation step and not aromatization of dihydrodiols derived from primary arene oxides. We propose a scheme for the in vitro synthesis of the catechol and hydroquinone metabolites, which may be precursors for electrophilic semiquinone or quinone products with the potential for cytotoxic and genotoxic effects.
Asunto(s)
Compuestos de Bifenilo/metabolismo , Catecoles/metabolismo , Hidroquinonas/metabolismo , Bifenilos Policlorados/metabolismo , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Cinética , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
A general and high-yielding synthetic route is presented by which a variety of chlorinated dihydroxybiphenyl metabolites may be synthesized. These synthetic standards will permit the investigation of novel pathways of polychlorinated biphenyl activation. The biphenyldiols were synthesized via palladium-catalyzed cross-coupling of dimethoxyphenylboronic acids with aryl bromides in the presence of a base. The formed dimethoxybiphenyls were demethylated using boron tribromide to yield the chlorinated dihydroxybiphenyls. These compounds were characterized by IR, NMR, and GC/MS.