Nuevos anticoagulantes orales en odontología: Dabigatran / New oral anticoagulants in dentist: Dabigatran

Introducción: El tratamiento con anticoagulantes se aplica en diferentes condiciones para prevenir o tratar el tromboembolismo. Los fármacos anticoagulantes se asocian con un incremento en el riesgo de hemorragia postoperatoria. La uS Food and Drug Administration y la Agencia Europea del Medicamento recientemente han indicado el uso de dabigatran etexilato como posible tratamiento para prevenir los accidentes cerebrovasculares y las embolias sistémicas en pacientes con fibrilación auricular. No precisan la realización de estudios periódicos de monitorización en comparación con los clásicos anticoagulantes. un inconveniente es que dabigatran no presenta antídotos. Conclusiones: El número de pacientes a los que se les administra dabigatran se está incrementando. Es importante que los odontólogos comprendan el mecanismo de acción de estos fármacos y cómo pueden repercutir en el manejo de los pacientes. Como profesionales sanitarios deben ser conscientes de cómo y cuándo reportar las reacciones adversas (AU)

Introduction: Anticoagulation therapy is used in different conditions to prevent or treat thromboembolism. Anticoagulant drugs have also been associated with an increase in the risk of postoperative hemorrhage. The uS Food and Drug Administration and the European Medicines Agency recently recommended dabigatran etexilate as a possible treatment to prevent stroke and systemic embolism in people with atrial fibrillation. There is no need for routine coagulation monitoring in the same way as classic oral anticoagulants. The disadvantage is that dabigatran have no antidotes. Conclusions: The number of patients taking dabigatran is increasing. It is important that the dentist understands the mechanism of action of these drugs and how they may affect management of dental patients. As healthcare professionals we should also be aware of how and when to report adverse drug reactions (AU)

Tratamiento con anticoagulantes orales: inicio, ajuste y precauciones en su utilización / Oral anticoagulant treatment: initiation, adjustment and use precautions

Los fármacos con actividad anticoagulante oral aprobados hasta el día de hoyprecisan de un especial manejo por sus características farmacocinéticas y farmacodinámicas.Corresponden al grupo de los dicumarínicos, cuyo mecanismode acción resulta de la interferencia en el metabolismo de los factores vitaminaK-dependientes. Existen guías de grupos de expertos con el objetivode facilitar unas normas para mejorar la seguridad de este tratamiento, dadaslas dificultades inherentes a sus características. El futuro se espera prometedorcon nuevos antitrombóticos, algunos de ellos ya aprobados para otras indicaciones,con un mejor perfil farmacológico que los diferencia de los dicumarínicos,especialmente porque no precisan controles analíticos y por la prácticaausencia de interacciones farmacológicas(AU)

The drugs with oral anticoagulant activity which up to today are approved aredrugs that require special handling due to their characteristics pharmacokineticsand pharmacodynamics. They correspond to the dicoumarin group, whosemechanism of action is interfering with the metabolism of vitamin K-dependentfactors. There are experts groups’ guidelines with the objective of providingstandards to improve safety of this treatment given the difficulties inherent inits characteristics. The future expects to be promising waiting for new antithrombotic,some of them already approved for other indications, with a betterpharmacological profile different to dicoumarin drugs, especially because theydon’t require follow-up analytical controls and the practical absence of druginteractions(AU)

Studies on the nitroreductase prodrug-activating system. Crystal structures of complexes with the inhibitor dicoumarol and dinitrobenzamide prodrugs and of the enzyme active form.

The E. coli nitroreductase enzyme (NTR) has been widely used in suicide gene therapy (GDEPT and ADEPT) applications as a activating enzyme for nitroaromatic prodrugs of the dinitrobenzamide class. NTR has been previously shown to be a homodimeric enzyme with two active sites. We present here the crystal structures of the reduced form of NTR and its complexes with the inhibitor dicoumarol and three dinitrobenzamide prodrugs. Comparison of the structures of the oxidized and reduced forms of the native enzyme shows that the principal structural changes occur in the FMN cofactor and indicate that the enzyme itself is a relatively rigid structure that primarily provides a rigid structural framework on which hydride transfer occurs. The aziridinyldinitrobenzamide prodrug CB 1954 binds in nonidentical ways in both of the two active sites of the homodimeric enzyme, employing both hydrophobic and (in active site B) a direct H-bond contact to the side chain of Lys14. In active site A the 2-nitro group stacks above the FMN, and in active site B the 4-nitro group does, explaining why reduction of either nitro group is observed. In contrast, the larger mustard group of the dinitrobenzamide mustard compound SN 23862 forces the prodrug to bind at both active sites with only the 2-nitro group able to participate in hydride transfer from the FMN, explaining why only the 2-hydroxylamine reduction product is observed. In each site, the nitro groups of the prodrug make direct H-bond contacts with the enzyme; in active Site A the 2-nitro to Ser40 and the 4-nitro to Asn71, while in active Site B the 2-nitro contacts the main chain nitrogen of Thr41 and the 4-nitro group the Lys14 side chain. The related amide-substituted mustard SN 27217 binds in a broadly similar fashion, but with the larger amide group substituent able to reach and contact the side chain of Arg107, further restricting the prodrug conformations in the binding site. The inhibitor dicoumarol appears to bind primarily by pi-stacking interactions and hydrophobic contacts, with no conformational changes in the enzyme. One of the hydroxycoumarin subunits stacks above the plane of the FMN via pi-overlap with the isoalloxazine ring, penetrating deep into the groove, with the other less well-defined. These studies suggest guidelines for further prodrug design. Steric bulk (e.g., mustard rather than aziridine) on the ring can limit the possible binding orientations, and the reducible nitro group must be located para to the mustard. Substitution on the carboxamide side chain still allows the prodrugs to bind, but also limits their orientation in the binding site. Finally, modulating substrate specificity by alteration of the structure of the enzyme rather than the prodrug might usefully focus on modifying the Phe124 residue and those surrounding it.

Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer.

This article investigates the effect of particle size and the incorporation of a bioadhesive polymer, poly(fumaric-co-sebacic) anhydride p(FA:SA), on the relative bioavailability of dicumarol. A novel method was used to reduce particle size of the drug, and encapsulated formulations were fabricated using a phase inversion technique to produce nanospheres and microspheres with varying size. Groups of Yorkshire swine were catheterized and gavaged after fasting for 12 h with each formulation in a 50 mg/mL suspension. Blood was collected at different time points, from 0 to 96 h, and pharmacokinetic analysis revealed that formulations incorporating the smaller drug particles showed the highest bioavailability: micronized drug with 7% p(FA:SA) 17:83 polymer had 190% relative bioavailability, and phase inverted p(FA:SA) 17:83 microspheres with 31% (w/w) loading had 198% relative bioavailability to spray dried formulation. Formulations with larger drug particles achieved 71% relative bioavailability. A nonadhesive formulation, fabricated with poly(lactic acid) (PLA), showed 91% relative bioavailability. Both particle size and polymer composition play a role in oral absorption of dicumarol.

Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride.

PURPOSE: This study was carried out to show the effect of particle size reduction and bioadhesion on the dissolution and relative bioavailability of dicumarol. METHODS: Formulations were produced by a variety of methods including a novel technique to reduce particle size as well as phase inversion with poly(fumaric-co-sebacic)anhydride p(FA:SA) to create nanospheres. Drug was administered to groups of pigs and rats via oral gavage of a suspension, and dicumarol concentration in the blood was measured using a double extraction technique. RESULTS: In vitro results showed improved dissolution in both the micronized formulation and the encapsulated p(FA:SA) nanospheres. In vivo, relative bioavailability of a spray-dried formulation was increased by 17% in the rat and 72% in the pig by further reduction in particle size. The bioadhesive p(FA:SA) formulation also improved relative bioavailability over the spray-dried drug, increasing it by 55% in the rat and 96% in the pig. Additionally, the p(FA:SA) formulation prolonged Tmax and decreased Cmax in both species. CONCLUSION: This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.

Manejo de la anticoagulación en pacientes con prótesis valvulares. Controversias / Management of anticoagulation in patients with prosthetic valves

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Structural and drug-binding properties of alpha(1)-acid glycoprotein in reverse micelles.

Alpha(1)-acid glycoprotein (AGP) is a glycoprotein that consists of 183 amino acid residues and five carbohydrate chains and binds to neutral and basic drugs. We examined the structural properties and ligand-binding capacity of AGP in interactions with reverse micelles. Also, detailed information was obtained by comparing several different states of AGP. Interaction with reverse micelles induced a unique conformational transition (beta-sheet to alpha-helices) in AGP and decreased the binding capacity for the basic drug, chlorpromazine and the steroid hormone, progesterone to AGP. These structural conformations are very similar to those observed under conditions of acidity and high ionic strength (pH 2.0, 1.5 M NaCl). This structure seems to be an intermediate between the native state and the denatured state, possibly a molten globule. The present results suggest that when AGP interacts with the biomembrane, it undergoes a structural transition to a unique structure that differs from the native and denatured states and has a reduced ligand-binding capacity.

Interaction of oral anticoagulants with methyl xanthines.

The interaction of warfarin and dicumarol with methyl xanthines was monitored. The results revealed formation of equimolar complexes with both caffeine and theophylline. The interaction is exothermic and complexation is thermodynamically unfavourable. The apparent solubility of dicumarol in water was found to increase linearly with increasing methyl xanthine concentration. The dissolution rate of the prepared complexes is higher than that of their respective physical mixtures or the respective drug per se. The implication of such interaction on the biological performance of the two anticoagulants was assessed in Albino rabbits. The results indicate that incorporation of dicumarol in form of a complex or even as a physical mixture with methyl xanthines does affect the biological performance of the drug to a marked extent.