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991.
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994.
Ramesh Gannu Vamshi Vishnu Yamsani Shravan Kumar Yamsani Chinna Reddy Palem Swathi Voruganti Madhusudan Rao Yamsani 《Journal of pharmaceutical and biomedical analysis》2009,50(5):1080-1084
A simple and sensitive reverse phase ultra fast liquid chromatographic (UFLC) method for simultaneous determination of nitrendipine and carvone in skin diffusate samples and microemulsions was developed and validated. The separation was achieved using a gradient mobile phase, on an Onyx column. The eluents were monitored by photodiode array detection. The linearity ranges of proposed method were 0.125–50 μg mL−1 and 0.125–30 μg mL−1 for nitrendipine and carvone respectively. The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 10%. The method was found to be precise, accurate, and specific during the study. The method was successfully applied for simultaneous estimation of nitrendipine and carvone in ex vivo skin diffusate samples and microemulsions. 相似文献
995.
Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase
Syamantak Majumder Megha Rajaram Ajit Muley Himabindu S Reddy KP Tamilarasan Gopi Krishna Kolluru Swaraj Sinha Jamila H Siamwala Ravi Gupta R Ilavarasan S Venkataraman KC Sivakumar Sharmila Anishetty Pradeep G Kumar Suvro Chatterjee 《British journal of pharmacology》2009,158(7):1720-1734
Background and purpose:
Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets.Experimental approach:
Cell-based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC).Key results:
Thalidomide inhibited pro-angiogenic functions in endothelial cell cultures, whereas 8-bromo-cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8-bromo-cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration-dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO-dependent angiogenesis.Conclusion and implications:
Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti-angiogenic effects. These results could lead to the formulation of thalidomide-based drugs to curb angiogenesis by targeting sGC. 相似文献996.
Hongliang Cai Arun K. Agrawal David A. Putt Muhammed Hashim Anita Reddy Joanne Brodfuehrer Narayanan Surendran Lawrence H. Lash 《Toxicology》2009
PF1, an anti-inflammatory drug candidate, was nephrotoxic in cynomolgus monkeys in a manner that was qualitatively comparable to that observed with the two previous exploratory drug candidates (PF2 and PF3). Based on the severity of nephrotoxicity, PF1 ranked between the other two compounds, with PF2 inducing mortality at all doses and PF3 eliciting only mild nephrotoxicity. To further characterize nephrotoxicity in monkeys and enable direct comparisons with humans, primary cultures of proximal tubular (PT) cells from monkey and human kidneys were used as in vitro tools, using lactate dehydrogenase release as the biomarker of cytotoxicity. In both human and monkey PT cells, PF2 was by far the most cytotoxic compound of the three drugs. PF1 exhibited modest cytotoxicity at the highest concentration tested in human PT cells but none in monkey kidney cells whereas PF3 exhibited the reverse pattern. Because these drugs are organic anions, mechanistic studies using human organic anion transporters 1 and 3 (hOAT1 and hOAT3) transfected cell lines were pursued to evaluate the potential of these compounds to interact with these transporters. All three drugs exhibited high affinity for hOAT3 (PF1 exhibited the lowest IC50 of 6 μM) but only weakly interacted with hOAT1 (with no interaction found for PF2). PF2 was a strong hOAT3 (not hOAT1) substrate, whereas PF1 and PF3 were substrates for both hOAT1 and hOAT3. Upon pretreatment of monkeys with the OAT substrate probenecid, PF3 systemic exposure (AUC) and half-life (t1/2) increased ∼2-fold whereas clearance (CL) and volume of distribution (Vdss) decreased, as compared to naïve monkeys. This indicated that PF3 competed with probenecid for hOAT1 and/or hOAT3 mediated elimination of PF3. Thus, hOAT1 and/or hOAT3 may be responsible for the uptake of this series of drugs in renal PT cells, which may directly or indirectly lead to the observed nephrotoxicity in vivo. 相似文献
997.
Nayak UY Gopal S Mutalik S Ranjith AK Reddy MS Gupta P Udupa N 《Journal of microencapsulation》2009,26(3):214-222
Zidovudine-Chitosan microspheres were prepared by a suspension cross-linking method. The chitosan was dissolved in 2% acetic acid solution and this solution was dispersed in the light liquid paraffin. Span-80 was used as an emulsifier and glutaraldehyde as cross-linking agent. The prepared microspheres were slight yellow, free flowing and characterized by drug loading, infrared spectroscopy (IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in-vitro release studies are performed in pH 7.4 buffer solution. Microspheres produced are spherical and have smooth surfaces, with sizes ranging between 60-210 μm, as evidenced by SEM and particle size analysis. The drug loaded microspheres showed up to 60% of entrapment and release was extended up to 18-24 h. Among all the systems studied, the 35% Glutaraldehyde crosslinked, microspheres with 1 : 6 drug/chitosan ratio showed 75% release at 12 h. The infrared spectra and DSC thermograms showed stable character of zidovudine in the drug loaded microspheres and revealed the absence of drug-polymer interactions. Data obtained from in vitro release were fitted to various kinetic models and high correlation was obtained in the Higuchi model. The drug release was found to be diffusion controlled. 相似文献
998.
Kannan Krishnan Lee C.B. Crouse Matthew A. Bazar Michael A. Major Gunda Reddy 《Journal of applied toxicology : JAT》2009,29(7):629-637
A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h?1 kg?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (Ka 0.75 h?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg?1) or lower doses (0.2 or 1.24 mg kg?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg?1 as well as oral doses ranging from 0.2 to 100 mg kg?1. Published in 2009 by John Wiley & Sons, Ltd. 相似文献
999.
Several new classes of benzimidazole derivatives were synthesized and evaluated for in‐vitro antimicrobial and cytotoxic activities. The results showed that all synthesized compounds exhibited moderate antimicrobial activity, and compounds 2 , 4 , and 13 displayed cytotoxic activity (as LD50) at the concentration 1×10–3 M against Artemia salina. 相似文献
1000.
Translocase I inhibitor compounds derived from capuramycin demonstrated rapid bactericidal activity against several different mycobacterial species. SQ641 was the most active of the compounds, with a MIC of 0.12 to 8 microg/ml, a postantibiotic effect of 55 h, and interesting synergistic effects with other antitubercular drugs. 相似文献