The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

Oxidative decomposition of toxic pollutants (such as acetaldehyde and isopropyl alcohol), decomposition of water, and photocurrent generation can all be achieved with visible light. Nano‐islands of p‐type CaFe2O4 interfacing with bulk n‐type PbBi2Nb1.9W0.1O9 (shown) form photocatalytic nanodiodes that demonstrate high stability and high activity for such applications.

ABSTRACT:The present study evaluates the impact of P-glycoprotein (P-gp) on plasma-brain disposition and transepithelial transport of sedating versus nonsedating H1-antagonists using multidrug-resistant (mdr) gene 1a and 1b (mdr1a/b) knockout (KO) mice and human MDR1-transfected Madin-Darby canine kidney (MDCK) cells. Three nonsedating (cetirizine, loratadine, and desloratadine) and three sedating (diphenhydramine, hydroxyzine, and triprolidine) H1-antagonists were tested. Each compound was administered to KO and wild-type (WT) mice intravenously at 5 mg/kg. Plasma and brain drug concentrations were determined by liquid chromatography-mass spectrometry analysis. Mean pharmacokinetic parameters (CL, V ss , and t 1/2 ) were obtained using WinNonlin. In addition, certirizine, desloratadine, diphenhydramine, and triprolidine (2 M) were tested as substrates for MDR1 using MDR1-MDCK cells. The bidirectional apparent permeability was determined by measuring the amount of compound at the receiving side at 5 h. The brain-to-plasma area under the curve (AUC) ratio was 4-, 2-, and >14-fold higher in KO compared with WT mice for cetirizine, loratadine, and desloratadine, respectively. In contrast, the brain-to-plasma AUC ratio between KO and WT was comparable for hydroxyzine, diphenhydramine, and triprolidine. Likewise, the efflux ratio between basolateral to apical and apical to basolateral was 4.6-and 6.6-fold higher in MDR1-MDCK than the parental MDCK for certirizine and desloratadine, respectively, whereas it was approximately 1 for diphenhydramine and triprolidine. Our results demonstrate that sedating H1-antagonists hydroxyzine, diphenhydramine, and triprolidine are not P-gp substrates. In contrast, nonsedating H1-antagonists cetirizine, loratadine, and desloratadine are P-gp substrates. Affinity for P-gp at BBB may explain the lack of central nervous system side effects of modern H1-antagonists.Antagonists of H1 histamine receptors (H1-antagonists) are the mainstays of treatment for a number of allergic disorders, particularly rhinitis, conjunctivitis, dermatitis, urticaria, and asthma. Two generations of H1-antagonists have been developed so far. The first generation H1-antagonists such as diphenhydramine (Benadryl), triprolidine (Actifed), or hydroxyzine (Atarx) produce histamine blockade at H1-receptors in the central nervous system (CNS 1 ) and frequently cause somnolence or other CNS adverse effects (Simons, 1999). Therefore, the first generation H1-antagonists are also referred to as sedating antihistamines. The second generation H1-antagonists such as cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), or desloratadine (Clarinex) represent an advance in therapeutics; in manufacturers' recommended doses, they produce relatively little somnolence or other CNS side effects (Kay and Harris, 1999). Therefore, the second generation H1-antagonists are frequently referred as nonsedating antihistamines. Evidence for this improvement in tolerance profile resulting from reduced CNS penetration has been li...

Recently developed lead‐free incipient piezoceramics are promising candidates for off‐resonance actuator applications with their exceptionally large electromechanical strains. Their commercialization currently faces two major challenges: high electric field required for activating the large strains and large strain hysteresis. It is demonstrated that design of a relaxor/ferroelectric composite provides a highly effective way to resolve both challenges. Experimental results in conjunction with numerical simulations provide key parameters for the development of viable incipient piezoceramics.

No abstract