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81.
MB Gill S Frausto M Ikoma M Sasaki M Oikawa R Sakai GT Swanson 《British journal of pharmacology》2010,160(6):1417-1429
Background and purpose:
A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these ‘IKM’ compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159.Experimental approach:
The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques.Key results:
The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2- and GluA4-containing α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [3H]-AMPA from receptor binding sites. IKM-159 reduced spontaneous action potential firing in both cultured hippocampal neurons in control conditions and during hyperactive states in an in vitro model of status epilepticus.Conclusions and implications:
IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes. 相似文献82.
GT Whiteside JM Dwyer JE Harrison CE Beyer T Cummons L Manzino L Mark GH Johnston BW Strassle A Adedoyin P Lu MJ Piesla CM Pulicicchio JCL Erve BJ Platt ZA Hughes KE Rogers DC Deecher EJ Trybulski JD Kennedy P Zhang L Leventhal 《British journal of pharmacology》2010,160(5):1105-1118
Background and purpose:
Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.Experimental approach:
In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).Key results:
WAY-318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.Conclusions and implications:
Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain. 相似文献83.
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86.
The effect of feed temperaturae and phototherapy on the rate of stomach emptying was studied in healthy infants during the first week. Emptying rate was measured by the modified serial test meal technique using 10% Dextrose feeds. The results show that emptying rate is independent of feed temperature and is not affected by phototherapy. 相似文献
87.
GT Lealman RW Logan JH Hutchison MM Kerr AM Fulton CA Brown 《Archives of disease in childhood》1976,51(5):377-384
Serial changes in plasma levels of calcium, phosphorus, magnesium, alkaline phosphatase, and total proteins have been investigated in 138 healthy, term Caucasian infants. Blood samples were obtained for each infant from cord blood and on day 1 and day 6. The infants were studied in three groups according to whether they were breast fed, received 'Ostermilk No. 1' or 'Cow and Gate V' formulas. Levels of calcium, phosphorus, magnesium, alkaline phosphatase, and total proteins did not differ between the groups at birth or on day 1. By day 6 calcium levels were higher and phosphorus levels lower in the breast-fed infants compared with either of the artificially-fed groups. Phosphorus levels were lower in the V Formula group compared with the Ostermilk group but the mean calcium levels of these two groups did not differ significantly. However, only 2-8% of the V Formula group developed hypocalcaemia compared with 18-2% of the Ostermilk group. The only infant developing clinical tetany belonged to the group fed Ostermilk. Evidence is also given which suggests that those infants with low calcium levels on day 1 who were fed the high-solute milk tended to show a fall in calcium by day 6. This did not apply to the two other groups. It is concluded that the use of adapted cows' milk preparations for infant feeding should lead to a reduction in the incidence of neonatal tetany. 相似文献
88.
Levin DN; Hu XP; Tan KK; Galhotra S; Pelizzari CA; Chen GT; Beck RN; Chen CT; Cooper MD; Mullan JF 《Radiology》1989,172(3):783-789
Three patients with intractable epilepsy, two with brain tumors, and one with encephalitis were imaged with magnetic resonance (MR) and positron emission tomography (PET). MR data were used to construct a three-dimensional (3D) computer model of the brain surface depicting the precentral (movement), postcentral (sensation), left inferior frontal (speech), and left superior temporal (hearing) gyri. PET-derived measurements of average surface metabolism were encoded as colors and mapped onto the 3D model by means of a retrospective technique for registering the two scans. The integrated 3D model depicted the location of PET-detected metabolic abnormalities with respect to the gyral anatomy visualized with MR. In each case, the predicted relationships were confirmed intraoperatively by means of inspection of the brain and electroencephalography. Multimodality 3D displays are likely to be particularly valuable for interpreting PET studies of epileptic patients and others with normal MR anatomy. 相似文献
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90.
A case of vertical transmission of hepatitis A virus infection 总被引:3,自引:0,他引:3
We present a case of hepatitis A infection in a 2.5-month-old male who became icteric after 18 d of birth. The diagnosis of hepatitis A was made by compatible clinical symptoms, laboratory results and liver biopsy showing evidence of hepatitis, and confirmed by detection of anti-HAV IgM antibodies. Because the mother had an acute icteric hepatitis A 1 week before delivery, and the viraemic phase of hepatitis A infection is very short, approximately 7 d, we suggest that the infant was infected by his mother, before birth. 相似文献