A Review on the New and Old Anticoagulants.

Anticoagulants serve as the primary strategy for the prevention and treatment of both arterial and venous thromboembolism. Anticoagulants disrupt coagulation by interfering at various points in the coagulation cascade. This class of medications does not lyse clots that already exist; rather, it prevents thrombus formation and prevents or slows the extension of an existing clot. For decades, the standard therapy for patients requiring oral anticoagulation was warfarin. However, due to some of the shortcomings of warfarin, including the need for continuous routine monitoring, longtime onset and offset of anticoagulation effect, major food and drug interactions, and high incidence of bleeding, newer agents, termed direct oral anticoagulants, or DOACs were developed. This article will provide a review of clinically important information regarding the most commonly used anticoagulants and their reversal agents.

Identification of a host cell target for the thiazolide class of broad-spectrum anti-parasitic drugs.

The thiazolide nitazoxanide (NTZ) and some derivatives exhibit considerable in vitro activities against a broad range of parasites, including the apicomplexans Neospora caninum and Toxoplasma gondii tachyzoites. In order to identify potential molecular targets for this compound in both parasites, RM4847 was coupled to epoxy-agarose and affinity chromatography was performed. A protein of approximately 35 kDa was eluted upon RM4847-affinity-chromatography from extracts of N. caninum-infected human foreskin fibroblasts (HFF) and non-infected HFF, but no protein was eluted when affinity chromatography was performed with T. gondii or N. caninum tachyzoite extracts. Mass spectrometry analysis identified the 35 kDa protein as human quinone reductase NQO1 (P15559; QR). Within 8h after infection of HFF with N. caninum tachyzoites, QR transcript expression levels were notably increased, but no such increase was observed upon infection with T. gondii tachyzoites. Treatment of non-infected HFF with RM4847 did also lead to an increase of QR transcript levels. The enzymatic activity of 6-histidine-tagged recombinant QR (recQR) was assayed using menadione as a substrate. The thiazolides NTZ, tizoxanide and RM4847 inhibited recQR activity on menadione in a concentration-dependent manner. Moreover, a small residual reducing activity was observed when these thiazolides were offered as substrates.

Characterization of two classes of small molecule inhibitors of Arp2/3 complex.

Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.

Mechanistic assessment of peptide reactivity assay to predict skin allergens with Kathon CG isothiazolinones.

Assessment of skin sensitization hazard of chemicals currently depends on in vivo methods. Considering the forthcoming European Union ban on in vivo testing of cosmetic/toiletry ingredients, the search for alternative non-animal approaches is an urgent challenge for investigators today. For the skin sensitization end-point the concept of protein/peptide haptenation, that could reflect the chemical modification of skin proteins, crucial to form immunogenic structures, has been used to develop in vitro assays to predict the sensitization potential of new chemicals. Using glutathione and nucleophile-containing synthetic peptides we confirmed previously the possibility to screen for skin sensitization potential by measuring peptide depletion following incubation with a set of allergens and non-allergens. In this paper, additionally to our model development work, we performed mechanistic based studies to confirm the peptide reactivity concept under the specific conditions used for haptens in the screening assay as they were somewhat different from the ones expected to happen in vivo. Following the reactivity toward the peptides of 13C labelled MI and MCI, models of true haptens, we showed that the initial step leading to the biological end-point was similar regardless the conditions used even if final adducts could be different. This confirmed the validity of the peptide reactivity concept as well as the choice made to look at peptide depletion rather than at adduct formation.

Synthesis and inhibitory activity of oligosaccharide thiazolines as a class of mechanism-based inhibitors for endo-beta-N-acetylglucosaminidases.

A facile synthesis of oligosaccharide-thiazoline derivatives of N-glycans as a novel class of inhibitors for endo-beta-N-acetylglucosaminidases was described. It was found that the external sugar residues on the N-glycan core could enhance the inhibitory potency. While the Manbeta1,4GlcNAc- and Man3GlcNAc-thiazolines were only moderate inhibitors, the large Man9GlcNAc-thiazoline demonstrated potent inhibitory activity, with an IC(50) of 0.22 and 0.42 microM against the Arthrobacter enzyme (Endo-A) and the human endo-beta-N-acetylglycosaminidase (hENGase), respectively. It was also observed that the oligosaccharide thiazolines could differentially inhibit endo-beta-N-acetylglucosaminidases from different sources. These oligosaccharide thiazolines represent the first class of endo-beta-N-acetylglucosaminidase inhibitors.

The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.

A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.

Differentiating members of the thiazolidinedione class: a focus on efficacy.

The thiazolidinediones (TZDs) or 'glitazones' are a new class of drug used for the treatment of type 2 diabetes. Although their precise mechanism of action is not known, TZDs target insulin resistance directly and thus tackle an underlying cause of the disease. Two TZDs are indicated for use in type 2 diabetes in the USA, pioglitazone and rosiglitazone. A third, troglitazone, has been associated with significant hepatotoxicity and has been withdrawn from use. In clinical trials, all three TZDs effectively lower blood glucose levels as monotherapy and in combination therapy with sulfonylureas, metformin and insulin. To date, head-to-head comparative studies with these agents have not been performed. It is difficult, therefore, to make direct comparisons of their efficacy since other variables, including baseline glucose levels and study design, can have a significant impact on treatment outcome. Despite this and in light of unique safety issues characterized with certain TZDs, it is useful to look closely at the efficacy data for these agents. It is not sufficient to assume that 'all glitazones are the same' because the studies have not yet been done to support this statement. This article will review what is known about the relative efficacy of the TZDs.

Differentiating members of the thiazolidinedione class: a focus on safety.

Troglitazone, rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) class - antidiabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. All three agents are believed to mediate their effects via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma). Despite this common mechanism of action, they all have unique chemical structures and receptor-binding affinities, and consequently, in addition to the class effects (probably mediated through PPAR gamma), each TZD has a unique safety profile. Side effects have been categorized as unique to individual TZDs, or common to the class of drug. Of the unique effects, the best characterized is hepatotoxicity, which has been associated specifically with troglitazone to date. Studies with rosiglitazone and pioglitazone indicate that hepatotoxicity is not a class effect. Further differences in the safety profiles of these agents arise because the oxidative metabolism for each agent occurs by distinct cytochrome pathways: troglitazone and pioglitazone involve CYP 3A4 and CYP 2C8 whereas rosiglitazone is principally metabolized by CYP 2C8. CYP 3A4 is involved in the metabolism of over 150 drugs, hence the potential for drug interactions with troglitazone and pioglitazone is much greater than with rosiglitazone. Class effects include edema, slight reductions in hemoglobin and hematocrit (due to hemodilution), weight gain and alterations in plasma lipid profiles. This article considers safety data obtained from both clinical trials and clinical practice as a means of differentiating among troglitazone, rosiglitazone and pioglitazone.

[The selective inhibition of cyclooxygenase isoforms: a new approach to the search for effective and safe nonsteroidal anti-inflammatory drug agents]. / Selektivnaia ingibitsiia izoform tsiklooksigenazy: novyi podkhod k izyskaniiu éffektivnykh i bezopasnykh nesteroidnykh protivovospalitel'nykh lekarstvennykh sredstv.

The author submits present-day data on mechanisms of action and clinical application of new drug preparations, NSAID, derivatives of enolic acid of the oxicam class, movalis, as one of their number (meloxicam, international name), of Boehringer Ingelheim (Germany). Clinical and pharmacological value is discussed of selective blockade of cyclogenase isoenzymes (COX)--COX1 and COX2 in the antiinflammatory effect and development of unfavourable side-effects.