Pharmacokinetics of a contraceptive patch (Evra/Ortho Evra) containing norelgestromin and ethinyloestradiol at four application sites. (49/945)

AIMS: To determine the pharmacokinetic profile of norelgestromin (NGMN) and ethinyloestradiol (EE) following application of the contraceptive patch, Evra/Ortho Evra, at each of four anatomic sites (abdomen, buttock, arm, and torso). METHODS: Thirty-seven healthy, nonpregnant women aged 20-45 years participated in this open-label, four-period crossover study. Subjects were randomized to one of four treatment (site of application) sequences. Each patch was worn for 7 days, with a 1 month washout between treatments. Blood samples were collected before and at various times up to 240 h after application of each patch. Serum samples were assayed for NGMN and EE by validated methods. RESULTS: The serum concentration reference ranges for NGMN and EE are 0.6-1.2 ng ml-1 and 25-75 pg ml-1, respectively, based on studies of the mean Cave of oral norgestimate 250 microg and EE 35 microg. For all application sites, mean concentrations of NGMN and EE remained within these ranges during the 7 day wear period. Absorption of NGMN and EE during patch application on the buttock, arm, and torso was equivalent. Absorption of NGMN and EE during patch application on the abdomen was approximately 20% less than observed for the other three sites, although mean serum concentrations were still within reference ranges. A previous study demonstrated therapeutic equivalence of patches worn on the abdomen vs other sites. CONCLUSIONS: Serum concentrations of NGMN and EE from the contraceptive patch remain within the reference ranges throughout the 7 day wear period, regardless of the site of application (abdomen, buttock, arm, or torso).  (+info)

GABA transporters regulate inhibition in the retina by limiting GABA(C) receptor activation. (50/945)

Inhibition is mediated by two classes of ionotropic receptors in the retina, GABA(A) and GABA(C) receptors. We used the GABA transport blocker NO-711 to examine the role of GABA transporters in shaping synaptic responses mediated by these two receptors in the salamander retinal slice preparation. Focal applications (puffs) of GABA onto GABA(C) receptors on bipolar cells terminals or GABA(A) receptors on ganglion cells elicited currents that were enhanced by NO-711, demonstrating the presence of transporters in the inner plexiform layer (IPL). IPSCs were evoked in bipolar and ganglion cells by puffing kainate into the IPL. NO-711 enhanced the IPSCs only in bipolar cells, suggesting that, when GABA uptake was blocked, the GABA(C) receptors were more strongly activated by spillover transmission than the GABA(A) receptors on ganglion cells. NO-711 enhanced the light-evoked IPSCs mediated by GABA(C) receptors on bipolar cell axon terminals, which resulted in reduced transmission between bipolar and ganglion cells. NO-711 also shifted the intensity-response relationship of the ganglion cell, reducing its sensitivity to light. Surround illumination has been shown by others to produce similar shifts in ganglion cell light sensitivity. Our results show that GABA transporters limit the extent of inhibitory transmission at the inner retina during light-evoked signal processing.  (+info)

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. (51/945)

Increased flux of glucose through the hexosamine biosynthetic pathway (HSP) is believed to mediate hyperglycemia-induced insulin resistance in diabetes. The end product of the HSP, UDP beta-N-acetylglucosamine (GlcNAc), is a donor sugar nucleotide for complex glycosylation in the secretory pathway and for O-linked GlcNAc (O-GlcNAc) addition to nucleocytoplasmic proteins. Cycling of the O-GlcNAc posttranslational modification was blocked by pharmacological inhibition of O-GlcNAcase, the enzyme that catalyzes O-GlcNAc removal from proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc). PUGNAc treatment increased levels of O-GlcNAc and caused insulin resistance in 3T3-L1 adipocytes. Insulin resistance induced through the HSP by glucosamine and chronic insulin treatment correlated with increased O-GlcNAc levels on nucleocytoplasmic proteins. Whereas insulin receptor autophosphorylation and insulin receptor substrate 2 tyrosine phosphorylation were not affected by PUGNAc inhibition of O-GlcNAcase, downstream phosphorylation of Akt at Thr-308 and glycogen synthase kinase 3 beta at Ser-9 was inhibited. PUGNAc-induced insulin resistance was associated with increased O-GlcNAc modification of several proteins including insulin receptor substrate 1 and beta-catenin, two important effectors of insulin signaling. These results suggest that elevation of O-GlcNAc levels attenuate insulin signaling and contribute to the mechanism by which increased flux through the HSP leads to insulin resistance in adipocytes.  (+info)

Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. (52/945)

In some nerve cells, activation of GABA(A) receptors by GABA results in phasic and tonic conductances. Transient activation of synaptic receptors generates phasic inhibition, whereas tonic inhibition originates from GABA acting on extrasynaptic receptors, like in cerebellar granule cells, where it is thought to result from the activation of extrasynaptic GABA(A) receptors with a specific subunit composition (alpha(6)beta(x)delta). Here we show that in adult rat hippocampal slices, extracellular GABA levels are sufficiently high to generate a powerful tonic inhibition in delta subunit-expressing dentate gyrus granule cells. In these cells, the mean tonic current is approximately four times larger than that produced by spontaneous synaptic currents occurring at a frequency of approximately 10 Hz. Antagonizing the GABA transporter GAT-1 with NO-711 (2.5 microM) selectively enhanced tonic inhibition by 330% without affecting the phasic component. In contrast, by prolonging the decay of inhibitory postsynaptic currents (IPSCs), the benzodiazepine agonist zolpidem (0.5 microM) augmented phasic inhibition by 66%, while leaving the mean tonic conductance unchanged. These results demonstrate that a tonic GABA(A) receptor-mediated conductance can be recorded from dentate gyrus granule cells of adult rats in in vitro slice preparations. Furthermore, we have identified distinct pharmacological tools to selectively modify tonic and phasic inhibitions, allowing future studies to investigate their specific roles in neuronal function.  (+info)

Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. (53/945)

BACKGROUND: Acute organophosphorus (OP) pesticide poisoning is widespread in the developing world. Standard treatment involves the administration of intravenous atropine and an oxime to counter acetylcholinesterase inhibition at the synapse, but the usefulness of oximes is uncertain. AIM: To assess the evidence on the use of oximes in OP poisoning. DESIGN: Systematic review. METHODS: We searched Medline, Embase, and Cochrane databases (last check 01/02/02) for 'organophosphate' or 'oxime' together with 'poisoning' or 'overdose'. We cross-referenced from other articles, and contacted experts to identify unpublished studies. A Web search engine [www.google.com] was also used, with the keywords 'organophosphate', 'oxime', and 'trial' (last check 01/02/02). RESULTS: We found two randomized controlled trials (RCTs) involving 182 patients treated with pralidoxime. The RCTs found no benefit with pralidoxime, and have been used to argue that pralidoxime should not be used in OP poisoning. DISCUSSION: The RCT authors must be congratulated for attempting important studies in a difficult environment. However, their studies did not take into account recently clarified issues regarding outcome, and their methodology is unclear. A generalized statement that pralidoxime should not be used in OP poisoning is not supported by the published results. Oximes may well be irrelevant in the overwhelming self-poisoning typical of the tropics, but a large RCT comparing the current WHO-recommended pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/h infusion) with placebo is needed for a definitive answer. Such a study should be designed to identify any patient subgroups that might benefit from oximes.  (+info)

Detection of Ni2+ by a dimethylglyoxime probe using attenuated total-reflection infrared spectroscopy. (54/945)

A new analytical approach for the detection of Ni2+ utilizing an attenuated total reflection (ATR) technique is discussed in this paper. Nickel detection was accomplished on a silicon ATR parallelogram crystal uniformly coated by a ca. 1.5-microm Nafion film embedded with dimethylglyoxime (DMG) probe molecules. The detection of Ni2+ is based on the appearance of a unique infrared absorption peak at 1572 cm(-1) that corresponds to the C=N stretching mode in the nickel dimethylglyoximate, Ni(DMG)2, complex. The suitable operational pH range for the nickel infrared sensor is between 6 - 8. High alkalinity in the sample solution causes a leaching of Ni(DMG)2. The detection limit of the nickel infrared sensor is 1 ppm in a sample solution of pH = 8. Interference studies revealed that Cu2+ could compete with Ni2+ for the DMG sites in the Nafion matrix. The new nickel detection methodology can be potentially utilized, after further improvement, in field analysis to locate hot spots contaminated with a high ppm of Ni2+.  (+info)

BetaCore, a designed water soluble four-stranded antiparallel beta-sheet protein. (55/945)

BetaCore is a designed approximately 50-residue protein in which two BPTI-derived core modules, CM I and CM II, are connected by a 22-atom cross-link. At low temperature and pH 3, homo- and heteronuclear NMR data report a dominant folded ('f') conformation with well-dispersed chemical shifts, i, i+1 periodicity, numerous long-range NOEs, and slowed amide hydrogen isotope exchange patterns that is a four-stranded antiparallel beta-sheet with nonsymmetrical and specific association of CM I and CM II. BetaCore 'f' conformations undergo reversible, global, moderately cooperative, non-two-state thermal transitions to an equilibrium ensemble of unfolded 'u' conformations. There is a significant energy barrier between 'f' and 'u' conformations. This is the first designed four-stranded antiparallel beta-sheet that folds in water.  (+info)

Prognostic significance of elevated troponin I after percutaneous coronary intervention. (56/945)

OBJECTIVES: We sought to assess the incidence and clinical significance of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI). BACKGROUND: Elevated creatine kinase-MB (CK-MB) is prognostically important after PCI, but the prognostic significance of elevated cTnI after PCI is uncertain. METHODS: In a prospective substudy of the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) trials, which randomized patients with acute coronary syndromes (ACS) to receive aspirin or sibrafiban, we measured cTnI (positive, > or =1.5 ng/ml) and CK-MB (positive, > or =7 ng/ml) in 481 patients with PCI. Samples were collected immediately before and at 0, 8 and 16 h after PCI and analyzed by a core laboratory. The primary end point was the Kaplan-Meier estimate of death, myocardial infarction or severe, recurrent ischemia at 90 days. RESULTS: Overall, 230 patients (48%) had elevated cTnI after PCI. Such patients underwent PCI sooner and were more likely to have coronary stenting. Elevated cTnI was associated with nonsignificantly higher risks of the primary end point (11.5% vs. 8.7%; p = 0.15) and of death (1.8% vs. 0.4%; p = 0.4) and a significantly higher risk of death or infarction (10.6% vs. 4.2%; p = 0.005). This pattern was more pronounced for patients who became positive only after PCI: primary end point, 20.7% vs. 10.1% for patients who remained negative after PCI (p = 0.05); death, 5.2% vs. 0% (p = 0.02); death or infarction, 18.1% vs. 4.1% (p = 0.007). CONCLUSIONS: Elevated cTnI, often observed after PCI in patients with ACS, is associated with worse 90-day clinical outcomes. This marker, therefore, is a useful prognostic indicator in such patients.  (+info)