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91.
DW Bonhaus KK Weinhardt M Taylor A DeSouza PM McNeeley K Szczepanski DJ Fontana J Trinh CL Rocha MW Dawson LA Flippin RM Eglen 《Canadian Metallurgical Quarterly》1997,36(4-5):621-629
The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described. 相似文献
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93.
Nuclear scintigraphy was used to assess digital perfusion before and after treatment in 10 horses with clinical and radiographic evidence of chronic laminitis. Horses were evaluated for lameness, degree of distal phalanx rotation, and heel-toe hoof wall growth ratio, and randomly divided into two treatment groups. Group 1 horses received only egg bar-heart bar shoeing; Group 2 underwent egg bar-heart bar shoeing and coronary grooving. Horses were re-evaluated for digital perfusion, lameness, degree of distal phalanx rotation, and hoof wall growth at 6 week intervals over the 18 week follow-up period. Prior to treatment, relative scintigraphic activity at the dorsal laminar area was decreased and relative scintigraphic activity at the toe and adjacent solar area was increased. Egg bar-heart bar shoeing was associated with significantly increased dorsal laminar scintigraphic activity and significantly decreased solar scintigraphic activity over the 18 week period. Coronary grooving, in combination with egg bar-heart bar shoeing, resulted in a significantly lower heel-toe hoof wall growth ratio but did not enhance digital perfusion. Seven of 10 (70%) horses were responsive to treatment, defined as an improvement in lameness by at least one grade. Horses that were refractory to treatment had significantly lower dorsal laminar scintigraphic activity and higher palmar coronary scintigraphic activity prior to treatment than horses that responded to treatment. Our results are the first to demonstrate that egg bar-heart bar shoeing is associated with improved dorsal laminar perfusion, and support the use of this technique. In addition, we found that pre-treatment nuclear scintigraphy was predictive of clinical outcome in horses with chronic laminitis treated with corrective shoeing. 相似文献
94.
MJ Gorman DW Severson AJ Cornel FH Collins SM Paskewitz 《Canadian Metallurgical Quarterly》1997,146(3):965-971
A Plasmodium-refractory strain of Anopheles gambiae melanotically encapsulates many species of Plasmodium, whereas wild-type mosquitoes are usually susceptible. This encapsulation trait can also be observed by studying the response of refractory and susceptible strains to intrathoracically injected CM-Sephadex beads. We report the results of broad-scale quantitative trait locus (QTL) mapping of the encapsulation trait using the bead model system. Interval mapping using the method of maximum likelihood identified one major QTL, Pen1. The 13.7-cM interval containing Pen1 was defined by marker AGH157 at 8E and AGH46 at 7A on 2R. Pen1 was associated with a maximum LOD score of 9.0 and accounted for 44% of the phenotypic variance in the distribution of phenotypes in the backcross. To test if this QTL is important for encapsulation of Plasmodium berghei, F2 progeny were infected with P. berghei and evaluated for degree of parasite encapsulation. For each of the two markers that define the interval containing Pen1, a significant difference of encapsulation was seen in progeny with at least one refractory allele in contrast with homozygous susceptible progeny. These results suggest that Pen1 is important for melanotic encapsulation of Plasmodium as well as beads. 相似文献
95.
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97.
ES Cleaveland DW Zaharevitz JA Kelley K Paull DA Cooney H Ford 《Canadian Metallurgical Quarterly》1996,223(3):654-659
A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L-dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors. 相似文献
98.
Despite the introduction in recent years of novel antifungal agents, the potency and broad spectrum of activity of amphotericin B have ensured that it remains the treatment of choice for most deep-seated mycoses. However, this agent is not without significant toxicity, particularly in patients who are already seriously ill and/or who are receiving other potentially nephrotoxic drugs. We review the various routes by which amphotericin B can be administered, focusing mainly on the intravenous route. The use of more rapid infusion rates, lipid-complexed preparations, sodium supplementation in salt-depleted patients and strategies to reduce the incidence of infusion-related reactions and nephrotoxicity are also considered. Finally, detailed recommendations for the administration of amphotericin B are provided. 相似文献
99.
100.
FG Gervais NA Thornberry SC Ruffolo DW Nicholson S Roy 《Canadian Metallurgical Quarterly》1998,273(27):17102-17108
Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals that emanate from focal adhesions via the clustering of transmembrane integrins by components of the extracellular matrix. We demonstrate that Fak is cleaved by caspases at two distinct sites during apoptosis. The sites were mapped to DQTD772, which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak during apoptosis separates the tyrosine kinase domain from the focal adhesion targeting (FAT) domain. The carboxyl-terminal fragments that are generated suppress phosphorylation of endogenous Fak and thus resemble a natural variant of Fak, FRNK, that inhibits Fak activity by preventing the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the suicide program by disabling the anti-apoptotic function of Fak. Interestingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an upstream site. This appears to be the first example of a caspase substrate where the cleavage sites are not conserved between species. 相似文献