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61.
Epidural,cerebrospinal fluid,and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids 总被引:5,自引:0,他引:5
Bernards CM Shen DD Sterling ES Adkins JE Risler L Phillips B Ummenhofer W 《Anesthesiology》2003,99(2):455-465
BACKGROUND: The pharmacokinetics of epidurally administered drugs has been the subject of many studies, yet drug concentration in the epidural space has never been measured. This study was undertaken to characterize the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids on the basis of measurement of drug concentration in each of these compartments after epidural administration. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil were administered epidurally in anesthetized pigs. Microdialysis was used to sample the epidural space and the cerebrospinal fluid for measurement of opioid concentration over time. Plasma samples were obtained from the central venous plasma and the epidural venous plasma. These data were used to calculate relevant pharmacokinetic parameters, including mean residence time, elimination half-lives, areas under the concentration versus time curves, clearance, and volume of distribution for each opioid in each compartment. RESULTS: Some of the more important findings were that the cerebrospinal fluid and plasma pharmacokinetics of the opioids did not parallel their epidural pharmacokinetics and that their hydrophobic character governed multiple aspects of their lumbar epidural pharmacokinetics. CONCLUSIONS: The findings indicate that the spinal pharmacokinetics of these drugs are complex and, in some ways, counterintuitive. Also, the bioavailability of opioids in the cerebrospinal fluid and epidural space is determined primarily by their hydrophobicity, with less hydrophobic drugs having greater bioavailability. 相似文献
62.
Bianco C Strizzi L Rehman A Normanno N Wechselberger C Sun Y Khan N Hirota M Adkins H Williams K Margolis RU Sanicola M Salomon DS 《Cancer research》2003,63(6):1192-1197
Human Cripto-1 (CR-1) is a member of the epidermal growth factor-Cripto FRL1 Cryptic family that has been shown to function as a coreceptor with the type I Activin serine-threonine kinase receptor ALK4 for the transforming growth factor beta-related peptide Nodal. However, CR-1 can also activate the mitogen-activated protein kinase and Akt pathways independently of Nodal and ALK4 by an unknown mechanism. Here, we demonstrate that CR-1 specifically binds to Glypican-1, a membrane-associated heparan sulfate proteoglycan, and activates the tyrosine kinase c-Src, triggering the mitogen-activated protein kinase and Akt signaling pathways. Finally, an active Src kinase is necessary for CR-1 to induce in vitro transformation and migration in mouse mammary epithelial cells. 相似文献
63.
Rasmussen SG Adkins EM Carroll FI Maresch MJ Gether U 《European journal of pharmacology》2003,479(1-3):13-22
Fluorescence spectroscopy techniques have proven extremely powerful for probing the molecular structure and function of membrane proteins. In this review, it will be described how we have applied a series of these techniques to the biogenic amine transporters, which are responsible for the clearance of dopamine, norepinephrine, and serotonin from the synaptic cleft. In our studies, we have focused on the serotonin transporter (SERT) for which we have established a purification procedure upon expression of the transporter in Sf-9 insect cells. Importantly, the purified transporter displays pharmacological properties in detergent micelles similar to that observed in membranes suggesting that the overall tertiary structure is preserved upon purification. Using this purified SERT preparation and the fluorescent cocaine analogue RTI-233 as a molecular reporter, we have been able to characterize the microenvironment of the cocaine-binding pocket. In current follow-up studies, we are attempting to map the relative position of this binding pocket using fluorescence resonance energy transfer (FRET) between RTI-233 and an acceptor fluorophore covalently attached to endogenous cysteines in the transporter. Finally, it will be described how we recently initiated the implementation of single-molecule confocal fluorescence spectroscopy techniques in our studies of the SERT. 相似文献
64.
Reece DE Foon KA Bhattarcharya-Chatterjee M Adkins D Broun ER Connaghan DG Dipersio JF Holland HK Howard DA Hale GA Klingemann HG Munn RK Raptis A Phillips GL 《Clinical breast cancer》2003,3(Z4):S152-S157
The results of cytotoxic therapy, including dose-intensive therapy requiring autologous stem cell transplantation (ASCT), have been disappointing in patients with metastatic breast cancer, as almost all patients eventually experience disease progression. There has been a renewed interest in immunotherapeutic strategies in this disease, including evaluation of several breast cancer vaccines. In the current study, we describe the results of a program in which the anti-idiotype breast cancer vaccine 11D10 (TriAb) was administered before and after ASCT in patients with metastatic breast cancer chemosensitive to previous conventional therapy. The toxicity of this approach was acceptable, and idiotype-specific humoral and T-cell proliferative responses were observed in the majority of patients within a few weeks post-ASCT. The actuarial 3-year overall survival rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32% (95% CI, 19%-45%). Multivariate analysis identified achievement of a strong antibody and cellular immune response to the vaccine as the only significant prognostic factors for outcome. The ability to reliably produce robust immune responses after ASCT is encouraging. Further studies are required to determine if the immune response mediates an antitumor benefit in these patients. 相似文献
65.
Smith AJ Alder L Silk J Adkins C Fletcher AE Scales T Kerby J Marshall G Wafford KA McKernan RM Atack JR 《Molecular pharmacology》2001,59(5):1108-1118
Inhibitory gamma-aminobutyric acid (GABA)(A) receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different alpha subunits in combination with beta3gamma2s was examined in stably expressed human recombinant GABA(A) receptors by measuring (36)Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the alpha3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABA(A) receptors (alpha1, alpha2, alpha3, alpha5), alpha5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at alpha3beta3gamma2s with nonselective agonist chlordiazepoxide was greater than at alpha1, alpha2, or alpha5 (P < 0.001). The presence of an alpha4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower alpha4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 +/- 12%), CGS8216 (56 +/- 6%), CGS9895 (65 +/- 6%), and the weak partial inverse agonist Ro15-4513 (87 +/- 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5alpha-pregnan-3alpha-ol-20-one, but the type of alpha subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at alpha4beta3gamma2s (226 +/- 10% increase in the EC(20) response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3. 相似文献
66.
67.
Ronald M Adkins Chad K Klauser Everett F Magann Julia Krushkal Theonia K Boyd John N Fain John C Morrison 《International journal of pediatric obesity》2007,2(3):130-137
OBJECTIVE: Circulating leptin levels positively correlate with adult BMI and size at birth. Previous studies found gender-specific associations between polymorphisms in the leptin gene and postnatal obesity-related traits or circulating leptin levels. We examined the relationships among leptin gene polymorphisms, size for gestational age, umbilical cord leptin, and gender. METHODS: Six single nucleotide polymorphisms (SNPs) were genotyped in the leptin gene in 261 newborns (72 low birth weight Caucasians, 189 randomly-selected African-Americans). In African-Americans, umbilical cord leptin and free testosterone levels were measured. Linear regression was used to identify significant predictors of size for gestational age or cord leptin levels and gender x genotype interaction effects. RESULTS: There is a significant interaction between gender and genotype at site -2548 (A/G). Among low birth weight Caucasians, the A allele was associated with an increase in female size for gestational age, while the A allele was associated with decreased male birth size. Among African-Americans, the A allele was associated with a decrease in umbilical cord leptin in females and with an increase in cord leptin in males. Cord testosterone levels were not a significant predictor of cord leptin levels either among all African-American newborns or among strata of -2548 genotypes and gender. CONCLUSION: In male and female fetuses, site -2548 of the leptin gene may differently affect the expression level of the leptin gene or the rate of fetal growth. This gender-specific effect does not appear to be mediated by the level of free testosterone at delivery. 相似文献
68.
69.
Stenosis of the of the external auditory canal is difficult to manage. Numerous surgical prodecures have been advocated for its correction and all function to varying degrees, but repeat stenosis remains a problem. Our experience, with the use of a superiorly based preauricular transposition flap in combination with an endaural and postauricular approach in 5 patients, 8 ears, is presented. In 3 patients, 5 ears, the stenosis was congenital; in 1 patient, 1 ear, traumatic; and in 1 patient, 2 ears, secondary to chronic external otitis. With a follow-up of 1 to 9 years, the functional and cosmetic results have been satisfactory in all cases. 相似文献
70.
Warren Y. Adkins 《The Laryngoscope》1977,87(11):1833-1835
Successful long-term middle ear ventilation was established in 12 patients with chronic eustachian tube hypofunction that had failed to respond to repeated myringotomy and tympanotomy tube insertions by conventional techniques. The 12 patients (13 ears) had insertion of an untrimmed large flange “Per-Lee” type tube through a posterior-inferior tympanomeatal flap approach. The flange extended under the long process of the malleus, and into the hypotympanum and middle ear opening of the eustachian tube. The stem of the tube was brought out through the inferior central pars tensa. All tubes have remained in place for more than three years without serious complications providing adequate middle ear ventilation and preventing adherence of the tympanic membrane to the promontory. 相似文献