Comparison of Clinical Efficacy and Safety of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients Undergoing Percutaneous Coronary Intervention.

Comparison of Clinical Efficacy and Safety of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients Undergoing Percutaneous Coronary Intervention.

Cardiovasc Drugs Ther. 2013 Jul 5;
Park MW, Jeong SH, Her SH, Kim PJ, Cho JS, Kim CJ, Chung WS, Seung KB, Yim HW, Chang K

A new polymeric salt form of clopidogrel, clopidogrel resinate (CR), is a resinate complex of the (+)-clopidogrel optical isomer wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups. CR was approved for marketing by the Korean Food and Drug Administration based on a Phase I bioequivalence study. However, no data are available regarding its impact on adverse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI).Clopidogrel bisulfate (CB) was used exclusively from January 2004 through April 2010, after which CR was exclusively administered from May 2010 through September 2011, in 8 centers. We categorized the overall population (N?=?10,487) into two groups according to the prescribed clopidogrel type: CB (n?=?9,127) or CR (n?=?1,360). To minimize the covariate imbalance and confounding in comparing CB and CR, we used a multivariable Cox proportional hazard regression model and the propensity score (PS) method to identify a 1:1 matched cohort (n?=?2,470). We compared cumulative adverse outcomes during a 1-year follow-up after PCI in the overall population and in the PS-matched cohort.In the overall population, there is no difference in the 1-year cumulative event rates between the two groups (CB : CR) : composite of any death, nonfatal myocardial infarction or stroke (6.0 % vs. 6.0 %, adjusted HR, 0.82; 95 % CI, 0.61-1.11, p?=?0.57), stent thrombosis (0.4 % vs. 0.2 %; adjusted HR, 0.40; 95 % CI, 0.09-1.72, p?=?0.31), and bleeding (0.9 % vs. 0.6 %; adjusted HR, 0.67; 95 % CI, 0.28-1.58, p?=?0.22). In the PS-matched cohort, the overall findings were consistent.In this large real-world PCI population, CR was as effective and as safe as CB in preventing adverse clinical outcomes. HubMed – drug


Target-directed catalytic metallodrugs.

Braz J Med Biol Res. 2013 Jul 2;
Joyner JC, Cowan JA

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements. HubMed – drug


Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma.

Nat Commun. 2013 Jul 5; 4: 2123
Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, Simons M, Bückers J, Low PS, Urlaub H, Gärtner J, Steinfeld R

Loss of folate receptor-? function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-?-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-?, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-?-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-?-positive exosomes. Loss of folate receptor-?-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-?-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-?-positive and -negative exosomes into mouse brains demonstrate folate receptor-?-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-?-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting. HubMed – drug