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931.
A Rapid Spectrofluorimetric Technique for Determining Drug-Serum Protein Binding Suitable for High-Throughput Screening 总被引:2,自引:0,他引:2
Parikh HH McElwain K Balasubramanian V Leung W Wong D Morris ME Ramanathan M 《Pharmaceutical research》2000,17(5):632-637
Purpose. To develop and validate a rapid method for determining thedissociation constants with which pharmaceutical candidates and drugsbind to serum albumin and to 1-acid glycoprotein with the goal ofdeducing the extent of binding.
Methods. The quenching of the intrinsic tryptophan fluorescence ofserum albumin and 1-acid glycoprotein was monitored byspectrofluorimetry and the data were used to calculate the apparent dissociationconstant. Sodium warfarin was used to probe the warfarin-binding siteof serum albumin and diazepam was used to probe the benzodiazepinebinding site. Additionally, the binding of sodium salicylate, phenylbutazone, sulfinpyrazone, iophenoxic acid, theophylline, chloramphenicol,acetaminophen, lithium chloride and ampicillin were also investigated.Chlorpromazine hydrochloride and imipramine hydrochloride wereused as probes for 1-acid glycoprotein. The assays were also extendedto the multiwell format. The quenching curves were fitted to thequadratic binding equation to determine the dissociation constants.
Results. Intrinsic fluorescence measurements are an excellent predictorof the drug binding to human serum albumin and to 1-acidglycoprotein. These measurements detect binding to the warfarin andbenzodiazepine binding sites of human serum albumin. The dissociation constantsestimated using the method compare favorably to the dissociationconstants previously reported by Epps et al. using extrinsic fluorescencemethodology, and the results correlate well with equilibrium dialysisusing drug displacement endpoints.
Conclusions. These measurements can be carried out with smallsamples and do not require separation of the bound and unbound species.Additionally, the proposed methods eliminate membrane separations,are not compound specific and do not require analyticalchromatography or mass spectrometry for quantitation. Spectrofluorimetry mayprove to be a useful method for rapidly determining the protein bindingof combinatorial libraries. 相似文献
932.
HER2/neu and the epidermal growth factor receptor (EGFR) are significantly overexpressed in several cancer cells. Overexpression of these two receptors accounts for progression of many types of cancer: breast, ovarian, skin, pancreas and brain. In recent years, several approaches to disable the receptor complexes have shown promise. Antibody-based therapy, kinase inhibitors and other inhibitors of signaling molecules are the major approaches. Our group developed the concept that an anti-p185HER2/neu monoclonal antibody might represent a therapeutic for cancer and this has culminated in a clinically useful therapeutic, the humanized monoclonal antibody Herceptin (trastuzumab). We have now developed a small-molecule form of an anti-HER2/neu peptidomimetic (AHNP) that exhibit functions comparable to those of the monoclonal antibody Herceptin. This approach may be considered a new paradigm in receptor-specific tumor therapeutics. A brief review of our approach in developing receptor-specific therapeutic agents for HER2/neu-related cancer is presented. 相似文献
933.
STUDY OBJECTIVE: To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs. DESIGN: Retrospective pharmacovigilance study. DATA SOURCE: United States Food and Drug Administration's Adverse Event Reporting System (AERS) database. INTERVENTION: We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D2-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D2 receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol. MEASUREMENTS AND MAIN RESULTS: To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event. Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (>10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors. CONCLUSION: Treatment with potent D2-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies. 相似文献
934.
Ueda K Kawashima H Ohtani S Deng WG Ravoori M Bankson J Gao B Girard L Minna JD Roth JA Kundra V Ji L 《Cancer research》2006,66(19):9682-9690
NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to be involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non-small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of -0.677 (P < 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle-mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2- to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nanoparticles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P < 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment. 相似文献
935.
Duntsch C Divi MK Jones T Zhou Q Krishnamurthy M Boehm P Wood G Sills A Moore BM 《Journal of neuro-oncology》2006,77(2):143-152
Summary
Objective To test in vitro and in vivo the safety and efficacy of a novel chemotherapeutic agent, KM-233, for the treatment of glioma.
Methods
In vitro cell cytotoxicity assays were used to measure and compare the cytotoxic effects of KM-233, Δ8-tetrahydrocannabinol (THC), and bis-chloroethyl-nitrosurea (BCNU) against human U87 glioma cells. An organotypic brain slice
culture model was used for safety and toxicity studies. A human glioma-SCID mouse side-pocket tumor model was used to test
in vivo the safety and efficacy of KM-233 with intratumoral and intra-peritoneal administration.
Results KM-233 is a classical cannabinoid with good blood brain barrier penetration that possesses a selective affinity for the CB2
receptors relative to THC. KM-233 was as efficacious in its cytotoxicity against human U87 glioma as Δ8-tetrahydrocannabinol, and superior to the commonly used anti-glioma chemotherapeutic agent, BCNU. The cytotoxic effects of
KM-233 against human glioma cells in vitro occur as early as two hours after administration, and dosing of KM-233 can be cycled without compromising cytotoxic efficacy
and while improving safety. Cyclical dosing of KM-233 to treat U87 glioma in a SCID mouse xenograft side pocket model was
effective at reducing the tumor burden with both systemic and intratumoral administration.
Conclusion These studies provide both in vitro and in vivo evidence that KM-233 shows promising efficacy against human glioma cell lines in both in vitro and in vivo studies, minimal toxicity to healthy cultured brain tissue, and should be considered for definitive preclinical development
in animal models of glioma. 相似文献
936.
Malmstrom K Kotey P McGratty M Ramakrishnan R Gottesdiener K Reicin A Wagner JA 《Journal of clinical pharmacology》2006,46(8):917-924
Intravenous lidocaine, a nonspecific Na-channel blocker, was used to assess the dental impaction model for evaluation of neuropathic pain drugs. Sixty patients, experiencing moderate or severe pain after removal of > or = 2 third molars, were randomized (2:2:1:1) to lidocaine (4 mg/kg; maximal dose 300 mg), oxycodone/acetaminophen (10/650 mg), placebo, and active placebo (diphenhydramine, 50 mg). Lidocaine provided a modest degree of pain relief. Predefined endpoints of total pain relief and sum of pain intensity at 2, 4, and 6 hours showed numerically, not statistically significantly, greater pain relief versus placebo. A significantly greater effect over placebo was observed in peak effect and at shorter time points (30 minutes and 1 hour), consistent with the pharmacokinetic profile (plasma concentration of approximately 2 mug/mL). Oxycodone/acetaminophen provided significantly greater analgesia versus placebo, validating study conduct, and significantly greater pain relief was observed versus lidocaine, which is consistent with a smaller portion of dental extraction pain being of neuropathic origin. 相似文献
937.
Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure 总被引:5,自引:0,他引:5
Nurkiewicz TR Porter DW Barger M Millecchia L Rao KM Marvar PJ Hubbs AF Castranova V Boegehold MA 《Environmental health perspectives》2006,114(3):412-419
The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and cardiovascular dysfunction is well known, but the systemic mechanisms that drive this effect remain unclear. We have previously shown that acute pulmonary exposure to PM impairs or abolishes endothelium-dependent arteriolar dilation in the rat spinotrapezius muscle. The purpose of this study was to further characterize the effect of pulmonary PM exposure on systemic microvascular function and to identify local inflammatory events that may contribute to these effects. Rats were intratracheally instilled with residual oil fly ash (ROFA) or titanium dioxide at 0.1 or 0.25 mg/rat 24 hr before measurement of pulmonary and systemic microvascular responses. In vivo microscopy of the spinotrapezius muscle was used to study systemic arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187 or iontophoretic abluminal application of the adrenergic agonist phenylephrine (PHE). Leukocyte rolling and adhesion were quantified in venules paired with the studied arterioles. Histologic techniques were used to assess pulmonary inflammation, characterize the adherence of leukocytes to systemic venules, verify the presence of myeloperoxidase (MPO) in the systemic microvascular wall, and quantify systemic microvascular oxidative stress. In the lungs of rats exposed to ROFA or TiO2, changes in some bronchoalveolar lavage markers of inflammation were noted, but an indication of cellular damage was not found. In rats exposed to 0.1 mg ROFA, focal alveolitis was evident, particularly at sites of particle deposition. Exposure to either ROFA or TiO2 caused a dose-dependent impairment of endothelium-dependent arteriolar dilation. However, exposure to these particles did not affect microvascular constriction in response to PHE. ROFA and TiO2 exposure significantly increased leukocyte rolling and adhesion in paired venules, and these cells were positively identified as polymorphonuclear leukocytes (PMNLs). In ROFA- and TiO2-exposed rats, MPO was found in PMNLs adhering to the systemic microvascular wall. Evidence suggests that some of this MPO had been deposited in the microvascular wall. There was also evidence for oxidative stress in the microvascular wall. These results indicate that after PM exposure, the impairment of endothelium-dependent dilation in the systemic microcirculation coincides with PMNL adhesion, MPO deposition, and local oxidative stress. Collectively, these microvascular observations are consistent with events that contribute to the disruption of the control of peripheral resistance and/or cardiac dysfunction associated with PM exposure. 相似文献
938.
Management of subtrochanteric femoral fractures and metastases using long proximal femoral nail 总被引:9,自引:0,他引:9
We report our initial experience with a new reconstruction nail, the long proximal femoral nail (L.PFN), in the treatment of subtrochanteric femoral fractures and metastases. We performed 52 L.PFN in 49 patients over a period of 18 months with an average follow-up period of 47.7 weeks. Group I consisted of 24 patients, who had L.PFN for traumatic subtrochanteric femoral fractures. Group II consisted of 25 patients, who had L.PFN for femoral metastases and pathological fractures. (Three bilateral.) In nine patients in group I, the fracture was extending to the intertrochnateric region with involvement of the piriformis fossa. Eight patients in group I had open reduction and cerclage cabling of the fracture prior to L.PFN. All the traumatic fractures in group I had united with an average time to union of 19.4 weeks. In eight operations there were technical difficulties with the insertion of proximal locking screws. Five patients in our series had complications but we had no mechanical failures of the implant. L.PFN is a reliable implant for subtrochanteric femoral fractures and metastases. We also showed that open reduction and cerclage cabling of unstable subtrochanteric fractures prior to nailing was not detrimental to fracture healing in our series. 相似文献
939.
Nirmalan PK Katz J Robin AL Krishnadas R Ramakrishnan R Thulasiraj RD Tielsch J 《The British journal of ophthalmology》2004,88(10):1237-1241
AIM: To determine utilisation of eye care services in a rural population of southern India aged 40 years or older. METHODS: 5150 subjects aged 40 years and older selected through a random cluster sampling technique from three districts in southern India underwent detailed ocular examinations for vision impairment, blindness, and ocular morbidity. Information regarding previous use of eye care services was collected from this population through a questionnaire administered by trained social workers before ocular examinations. RESULTS: 3476 (72.7%) of 5150 subjects examined required eye care examinations. 1827 (35.5%) people gave a history of previous eye examinations, primarily from a general hospital (n = 1073, 58.7%). Increasing age and education were associated with increased utilisation of eye care services. Among the 3323 people who had never sought eye care, 912 (27.4%) had felt the need to have an eye examination but did not do so. Only one third of individuals with vision impairment, cataracts, refractive errors, and glaucoma had previously utilised services. CONCLUSIONS: A large proportion of people in a rural population of southern India who require eye care are currently not utilising existing eye care services. Improved strategies to improve uptake of services is required to reduce the huge burden of vision impairment in India. 相似文献
940.
PURPOSE: Eales' disease (ED) is an idiopathic retinal vasculitis condition, which affects the retina of young adult males. Retinal changes include perivasculitis, non-perfusion and neovascularization. Disruption of blood-retinal barrier (BRB) is the common feature in intra-ocular inflammatory diseases. Disruption of BRB results in vascular hyper permeability and infiltration of circulating leukocytes into the retinal parenchyma. Monocyte (MC) activation results in oxidant thrust and subsequent tissue damage. This has been reported in various intra-ocular inflammatory diseases such as uveitis and Behcet's disease. However, there are no such reports available in ED. Hence in the present study we have investigated the role of MC activation and hydroxyl radicals (OH) production and its possible involvement in promoting the development of retinal vasculitis in patients with ED. METHODS: Twelve patients with ED and twelve healthy volunteers were recruited for the study. MC was separated from their peripheral blood. MC from patients with ED and control subjects was stimulated with phorbol-12-myristate-acetate (PMA) and OH generated was analyzed using an electron spin resonance spectrometer (ESR). Superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), and iron content was determined in MC to assess the oxidant thrust and antioxidant defense. RESULTS: OH generation was elevated in MC from patients with ED, which coincided with diminished SOD activity and elevated levels of iron and TBARS, when compared with healthy control subjects. OH generation was abrogated when MC from ED were co-incubated with PMA and iron chelators such as diethylenetriaminepentacetic acid (DTPA) and desferrioxamine. Iron chelation also inhibited TBARS accumulation restored SOD activity in MC of patients with ED. CONCLUSIONS: For the first time we have demonstrated the production of OH generation in MC of patients with ED using ESR. Further we have shown the beneficial effect of iron chelation in mitigating free radical mediated changes in cellular metabolism. Based on our findings, we provide further evidence for the role of oxidant thrust in promoting retinal tissue damage in patients with ED. 相似文献