Stereo- and Regioselective Direct Multi-Deuterium-Labeling Methods for Sugars.
Stereo- and Regioselective Direct Multi-Deuterium-Labeling Methods for Sugars.
Filed under: Drug and Alcohol Rehabilitation
Chemistry. 2012 Nov 13;
Sawama Y, Yabe Y, Iwata H, Fujiwara Y, Monguchi Y, Sajiki H
Deuterium-labeled sugars can be utilized as powerful tools for the architectural analyses of high-sugar-containing molecules represented by the nucleic acids and glycoproteins, and chiral building blocks for the syntheses of new drug candidates (heavy drugs) due to their potential characteristics, such as simplifying the (1) H?NMR spectra and the stability of C?D bonds compared with C?H bonds. We have established a direct and efficient synthetic method of deuterated sugars from non-labeled sugars by using the heterogeneous Ru/C-catalyzed H-D exchange reaction in D(2) O under a hydrogen atmosphere with perfect chemo- and stereoselectivities. The direct H-D exchange reaction can selectively proceed on carbons adjacent to the free hydroxyl groups, and the deuterium labeling of various pyranosides (such as glucose and disaccharides), as well as furanosides, represented by ribose and deoxyribose was realized. Furthermore, the desired number of deuterium atoms can be freely incorporated into selected positions by the site-selective protection of the hydroxyl groups using acetal-type protective groups because the deuterium exchange reaction never proceeds on positions adjacent to the protected hydroxyl groups.
HubMed – drug
Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin.
Filed under: Drug and Alcohol Rehabilitation
J Pharm Sci. 2012 Nov 13;
Assumpção JU, Campos ML, Ferraz Nogueira Filho MA, Pestana KC, Baldan HM, Formariz Pilon TP, de Oliveira AG, Peccinini RG
Doxorubicin (DOX) is an anthracycline antibiotic with a broad antitumor spectrum. However, the clinical use of DOX is limited because of its cardiotoxicity, a dose-dependent effect. Colloidal drug delivery systems, such as microemulsions (MEs), allow the incorporation of drugs, modifying the pharmacokinetic (PK) profile and toxic effects. In this study, we evaluated the PK profile and cardiotoxicity of a new DOX ME (DOX-ME). The PK profile of DOX-ME was determined and compared with that of the conventional DOX after single-dose administration (6?mg/kg, intravenous) in male Wistar rats (n = 12 per group). The cardiotoxicity of DOX formulations was evaluated by serum creatine kinase MB (CKMB) activity in both animal groups before and after drug administration. The plasma DOX measurements were performed by high-performance liquid chromatography with fluorescence detection, and the CKMB levels were assayed using the CKMB Labtest® kit. The ME system showed a significant increase in plasma DOX concentrations and lower distribution volume when compared with conventional DOX. Serum CKMB activity increased after conventional DOX administration but was unchanged in the DOX-ME group. These results demonstrate modifications in drug access to susceptible sites using DOX-ME. DOX-ME displayed features that make it a promising system for future therapeutic application. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
HubMed – drug
Design of alginate-based aerogel for nonsteroidal anti-inflammatory drugs controlled delivery systems using prilling and supercritical-assisted drying.
Filed under: Drug and Alcohol Rehabilitation
J Pharm Sci. 2012 Nov 13;
Gaudio PD, Auriemma G, Mencherini T, Porta GD, Reverchon E, Aquino RP
In this study, a novel preparation method for alginate-based aerogels charged with nonsteroidal anti-inflammatory drugs (NSAIDs) was developed using prilling in combination with supercritical fluid technique. Nanoporous carriers were prepared by laminar jet breakup of drug/alginate solutions or suspensions followed by cross-linking in ethanol or aqueous CaCl(2) solutions, water replacement, and supercritical-CO(2) -assisted drying. A substantial drug loss was observed for highly soluble ketoprofen lysinate, whereas encapsulation efficiency was satisfying for slightly soluble ketoprofen. The tandem technique successfully produced almost spherical aerogels (sphericity coefficient 0.97-0.99) in narrow size distribution with reduced particle shrinkage and smooth surface (surface roughness 1.10-1.13); the internal porous texture of the parent hydrogels was preserved and appeared as a network of nanopores with diameters around 200?nm. Drug release profiles were monitored using a pH change method to evaluate the possible application of the aerogels as fast dissolving NSAIDs formulation. Aqueous cross-linking led to aerogels encapsulating ketoprofen in the amorphous form and with an enhanced burst effect in simulated gastric fluid (75% in 30?min), whereas ethanol cross-linking produced aerogels embedding drug in crystal clusters with slower dissolution rate. The system appears an interesting potential carrier for the fast delivery of slightly soluble drugs in the upper gastrointestinal tract. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
HubMed – drug
Hepatic Cyp2d and Cyp26a1 mRNAs and Activities are Increased During Mouse Pregnancy.
Filed under: Drug and Alcohol Rehabilitation
Drug Metab Dispos. 2012 Nov 13;
Topletz A, Le HN, Lee N, Chapman JD, Kelly EJ, Wang J, Isoherranen N
There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (p <0.05) on gestational days (GD) 15 and 19 compared to the non-pregnant controls. There was no change (p>0.05) in Cyp2d9 and Cyp2d10 mRNA. In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2.7-fold (p <0.05) on GD19 (56.8±39.4 pmoles/min/mg protein) when compared to the non-pregnant controls (20.8±11.2 pmoles/min/mg protein). An increase in Cyp26a1 mRNA (10-fold) and Rar? mRNA (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rar? mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy. A putative retinoic acid response element (RARE) was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (p<0.05) with Cyp26a1 and Rar?. These results show that Cyp2d mRNA is increased during mouse pregnancy and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy. Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy. HubMed – drug
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