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11.
K A Reddy B B Lohray V Bhushan A S Reddy N V Rao Mamidi P P Reddy V Saibaba N J Reddy A Suryaprakash P Misra R K Vikramadithyan R Rajagopalan 《Journal of medicinal chemistry》1999,42(17):3265-3278
Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile. 相似文献
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Lorenz M Evering WE Provencher A Blue JT Lewis HB Hazelette JR Rajagopalan P Meunier PC Car BD 《Toxicology and applied pharmacology》1999,155(3):227-236
DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406. Neither size nor number of erythroid or myeloid CFUs differed between cultures containing control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 microg/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity. 相似文献
13.
Kumar Rajagopalan David Peereboom G. Thomas Budd Thomas Olencki Siva Murthy Paul Elson Denise McLain Ronald Bukowski 《Investigational new drugs》1999,16(3):255-258
Circadian administration of chemotherapy has been reported to decrease toxicity and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable patients with progressive, hormone-refractory metastatic prostate cancer were treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug was delivered through a central venous catheter using a CADD-Plus computerized pump such that approximately 70% of the drug was administered between 3 and 9 p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of FUDR was 0.15 mg/kg/day × 14 days every 4 weeks. A total of 79 complete cycles was administered.Two of 18 evaluable patients (11.1%) had decreases in PSA lasting five and eight months. No objective responses or improvement in bone scans was noted. The major toxicity observed was diarrhea. Although circadian infusion FUDR is feasible and tolerable, it has limited activity in hormone refractory prostate cancer. 相似文献
14.
Krithika Rajagopalan PhD Linda Abetz MA Polyxane Mertzanis MPH Derek Espindle MA Carolyn Begley OD MS Robin Chalmers OD Barbara Caffery OD MS Christopher Snyder OD MS J. Daniel Nelson MD Trefford Simpson PhD Timothy Edrington OD MS 《Value in health》2005,8(2):168-174
OBJECTIVE: The purpose of this study was to compare the discriminative properties of two generic health-related quality of life (QoL) instruments (SF-36 and EQ-5D) and a newly developed disease-specific patient-reported outcomes instrument (Impact of Dry Eye on Everyday Life (IDEEL)) to distinguish between different levels of dry eye severity. METHODS: Assessment of 210 people: 130 with non-Sjogren's Keratoconjunctivitis Sicca (non-SS KCS), 32 with Sj?gren's Syndrome (SS) and 48 controls; comparison of SF-36, EQ-5D, and IDEEL age-adjusted data by dry eye severity levels. Severity was assessed based on diagnosis (non-SS KCS, SS, control), patient-report (none, very mild, mild, moderate, severe, extremely severe) and clinician-report (none, mild, moderate, severe). RESULTS: Discriminative validity results were consistent for all instruments. Significant differences between severity levels were found with most SF-36 scales (P < 0.05), all EQ-5D scales (P < 0.05), and all IDEEL scales (P < 0.0001), except for Treatment Satisfaction. IDEEL scales consistently outperformed the generic QoL measures regardless of the severity criterion used. Most SF-36 scales outperformed the EQ-5D QoL scale, but the EQ-5D visual analog scale outperformed the SF-36 scales, except for General Health Perceptions. CONCLUSIONS: The disease-specific IDEEL scales are better able to discriminate between severity levels than the majority of the generic QoL scales. Preliminary evidence demonstrates that the IDEEL will be sensitive to QoL changes over time, although further testing in controlled longitudinal studies is needed. 相似文献
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The burden of diabetes is expected to rise from 415 million individuals in 2015 to 642 million individuals by 2040. Most individuals pass through a phase of prediabetes before developing full-blown diabetes. Insulin resistance, impaired incretin action, and insulin hypersecretion are central to the pathophysiology of prediabetes. Individuals older than 40 years of age and other high-risk individuals should be screened for diabetes with fasting plasma glucose and/or hemoglobin A1c. For those diagnosed with prediabetes, the goal of treatment should be restoring euglycemia, because there are data showing that restoring normoglycemia during prediabetes and early diabetes can produce lasting remission. The preferred approach for this is intensive lifestyle intervention, which besides reducing progression to diabetes, has also been shown to reduce all-cause mortality in a long-term follow-up study. The best evidence for a pharmacological approach is with metformin. Other drugs that have shown efficacy include thiazolidinediones, alpha-glucosidase inhibitors, orlistat, basal insulin, and valsartan. However, except for metformin, none of these drugs are currently recommended for this purpose. Newer agents such as glucagon-like peptide-1 agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors also have considerable promise in this area. Bariatric surgery can be offered to patients with metabolic syndrome and body mass index of 30-35. 相似文献
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Rajagopalan S Brook R Mehta RH Supiano M Pitt B 《The American journal of cardiology》2002,89(5):562-566
Aging is associated with progressive deterioration in endothelial function. We hypothesized that losartan may represent a useful therapeutic strategy to ameliorate endothelial function in aged subjects. Eighteen healthy older subjects (mean age 75 +/- 3 years) were prospectively randomized in a double-blind, crossover fashion to receive either losartan 50 mg/day or placebo for 6 weeks. Subjects were switched to the opposite arm after a 2- week washout period. Flow-mediated dilation (FMD) in the brachial artery and plasma levels of vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM), moncocyte chemoattractant 1 protein, and E-selectin were measured in both arms at the beginning and end of the 6-week period. Losartan resulted in a 6-mm Hg decrease in systolic blood pressure (from 130 +/- 12 to 124 +/- 13 mm Hg), which was no different from placebo (132 +/- 12 to 127 +/- 13 mm Hg). FMD increased from 3.1 +/- 0.6% to 3.9 +/- 0.6% after losartan, and decreased from 3.3 +/- 0.3% to 2.4 +/- 0.6% after placebo (p = NS for both). In contrast, losartan reduced circulating concentrations of vascular cell adhesion molecule 1 (750 +/- 73 to 572 +/- 39), ICAM (405 +/- 26 to 196 +/- 10), and moncocyte chemoattractant 1 protein (560 +/- 56 to 423 +/- 35) (p <0.01 for all by analysis of variance), but not E-selectin. On univariate analyses, the strongest predictor of baseline endothelial function and change in FMD with losartan was low-density lipoprotein. There was a negative correlation between baseline endothelial function and change in FMD in response to losartan (r(2) = -0.75, p = 0.0003). Baseline ICAM levels alone significantly correlated with low-density lipoprotein cholesterol (r(2) = 0.54, p = 0.02) and weakly correlated with total cholesterol (r(2) = 0.47, p = 0.05). Thus, administration of losartan for a duration of 6 weeks has favorable effects on inflammatory markers in healthy older subjects, but does not alter peripheral conduit endothelial function. 相似文献
20.
Activity of the purified mutagenesis proteins UmuC, UmuD'', and RecA in replicative bypass of an abasic DNA lesion by DNA polymerase III. 总被引:4,自引:3,他引:4
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M Rajagopalan C Lu R Woodgate M O''''Donnell M F Goodman H Echols 《Proceedings of the National Academy of Sciences of the United States of America》1992,89(22):10777-10781
The introduction of a replication-inhibiting lesion into the DNA of Escherichia coli generates the induced, multigene SOS response. One component of the SOS response is a marked increase in mutation rate, dependent on RecA protein and the induced mutagenesis proteins UmuC and UmuD. A variety of previous indirect approaches have indicated that SOS mutagenesis results from replicative bypass of the DNA lesion by DNA polymerase III (pol III) holoenzyme in a reaction mediated by RecA, UmuC, and a processed form of UmuD termed UmuD'. To study the biochemistry of SOS mutagenesis, we have reconstituted replicative bypass with a defined in vitro system containing purified protein and a DNA substrate with a single abasic DNA lesion. The replicative bypass reaction requires pol III, UmuC, UmuD', and RecA. The nonprocessed UmuD protein does not replace UmuD' but inhibits the bypass activity of UmuD', perhaps by sequestering UmuD' in a heterodimer. Our experiments demonstrate directly that the UmuC-UmuD' complex and RecA act to rescue an otherwise stalled pol III holoenzyme at a replication-blocking DNA lesion. 相似文献