Comparative pharmacology of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

There are 5 BCR/ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML): bosutinib, ponatinib, imatinib, nilotinib and dasatinib. The availability of several therapeutic options raises the possibility of individualizing patient treatment. When evaluating patients’ individual pharmacological profiles, it is important to take into account the differences in the chemical structures of the drugs. Bosutinib, which has a unique interaction and safety profile, is a quinazoline, unlike the other TKIs that have a pyrimidine structure. All 5 TKIs inhibit the BCR/ABL tyrosine kinase, although only ponatinib is active against the strains expressing the T315I mutation. In addition, the 5 TKIs are generally non-selective drugs that can also inhibit other tyrosine kinases, such as cKIT or PDGFR, leading to both benefits in the treatment of some gastrointestinal tumors as well as additional adverse events. These drugs are orally administered and show moderate bioavailability, a large volume of distribution, high protein binding, and elimination after intense metabolism involving various Cytochrome P450 (CYP). They are also substrates of transport proteins and interact with inducers and inhibitors. All TKIs, except bosutinib, can inhibit the activity of transport proteins, leading to important drug interactions. As such, bosutinib is the drug with the better pharmacological profile. There is a close relationship between drug concentration and the beneficial/toxic effects of imatinib, nilotinib, and dasatinib. Therefore, plasma levels should be monitored to optimize patient treatment. Currently, there is no information for ponatinib. Overall, there is a high incidence of adverse events; although these do not usually lead to treatment discontinuation. All 5 TKIs have a similar safety profile; however, each TKI has unique adverse events. Pharmacological differences can identify the drug that is best suited to each patient, helping optimize CML therapy

Los apéndices tipo asta del ciervo primitivo Dicrocerus elegans: morfología, ciclo de crecimiento, ontogenia y dimorfismo sexual

Males and many females of the primitive deer Dicrocerus elegans from Sansan (Middle Miocene, France) bore antler-like appendages consisting of a simple-branched protoantler growing from a rather long pedicle and are decorated with ridges and furrows. The protoantler capacity to be rejected and subsequently re-grow is clearly evidenced by the presence of both pedicle and protoantler cast specimens. The youngest appendage is a long, laterally flattened shaft whose apex is usually forked with no appreciable limit between the pedicle and the protoantler. In females, the anterior and posterior appendage margins form a more acute angle than that of males, and are more parallel when viewed laterally. After the first casting, the protoantler base is larger than the pedicle top and a coronet-like structure appears developed only around the medial side. With successive castings, the pedicles become shorter and their section is more circular, while protoantlers become much bigger, and have much longer and more separated branches. Branches of females are shorter than those of males, especially the anterior one, and appear in a straight line, instead of being bent. In oldest appendages, the branches are shorter and more similar in size. Accessory branches and irregularities of this basic morphology are common. The separation between both sex morphotypes appears clearly evidenced by Discriminant and Principal Component Analyses. Histological features point to important differences with true antlers and suggest that casting could not occur annually. A core of spongy bone trabeculae is not developed. Once growth is completed, the mineralization progress from the core to the periphery and when the final ‘velvet’ protoantler becomes completely petrified, the tissues dies and the velvet-like skin is cleaned. A high degree of both wear and polish of the branch apices evidence the hard, bare, dead protoantler phase before casting. Due to the complete growth cycle and the presence of the coronet-like structure, Dicrocerus protoantlers and antlers seem to be homologous appendages. Histological differences could be related to differences in hormonal cycle regulation that can be caused by the fact that i) Dicrocerus inhabited a tropical environment, and ii) females also developed protoantlers. It should not be overlooked that true antlers appear several million years later in time than the development of protoantlers and other cranial appendages in ruminants, and coinciding with the Middle Miocene Climatic Transition.Tanto los machos como muchas de las hembras del ciervo primitivo Dicrocerus elegans de Sansan (Mioceno Medio, Francia) poseían apéndices craneales de tipo asta que consisten en una protoasta bifurcada y ornamentada con surcos y crestas que es sustentada por un pedículo moderadamente largo. La capacidad de la protoasta de ser expulsada y regenerada es evidente a partir de los ejemplares de desmogue y también por las diferencias histológicas existentes entre la protoasta y el pedículo. El primer apéndice consiste en una vara larga, comprimida lateralmente, y con el ápice bifurcado, sin que se observe ningun límite apreciable entre la protoasta y el pedículo. En las hembras, el ángulo que forman los margenes anterior y posterior del apéndice es más agudo que en los machos (los márgenes son más paralelos en vista lateral). Tras el primer desmogue, la base de la protoasta es más amplia que la sección distal del pedículo, y se desarrolla una estructura similar a la roseta en la parte medial. Con los sucesivos desmogues, el pedículo se acorta y su sección se hace más circular, mientras que la protoasta es cada vez más grande y las ramas son más largas y parten más separadas desde la base sin interposición de un tramo basal. En las hembras, las ramas son más cortas, especialmente la anterior, y su trazado es rectilíneo en vez de curvo como en los machos. En los ejemplares seniles, las ramas son más cortas y de longitud más similar entre ellas. Es frecuente la presencia de ramas accesorias, así como irregularidades de este patrón básico. Los análisis discriminantes y de componentes principales realizados muestran una clara separación entre los morfotipos atribuidos a machos y a hembras. Existen importantes diferencias histológicas con las verdaderas astas que sugieren que el desmogue podría no haber sido anual. Se confirma que no se desarrolla hueso esponjoso y que la mineralización del protoasta progresa centrífugamente desde el centro hasta la periferia. El desmogue tiene lugar una vez que los tejidos están completamente mineralizados (muertos). A diferencia de otras protoastas, el ciclo en Dicrocerus era completo dado que están documentadas tanto la fase de muda del terciopelo, como la de exposición del hueso desnudo antes del desmogue. Dadas las similitudes en el ciclo de crecimiento, y dado que la base de la protoasta presenta parcialmente una estructura similar a la roseta, las protoastas de Dicrocerus y las astas parecen ser apéndices homólogos. Las diferencias histológicas podrían estar relacionadas con diferencias en el ciclo hormonal que regulaba su crecimiento. Diferencias que podrían guardar relación con el hecho que i) Dicrocerus vivió en ambientes tropicales, ii) las hembras también poseían protoastas. Cabe resaltar que las verdaderas astas aparecieron varios millones de años más tarde de que surgieran las protoastas y otros apéndices craneales en Ruminantia, y en coincidencia con la transición climática del Mioceno Medio

Farmacología de los azoles

Azole antifungals have different pharmacokinetic characteristics: complete oral absorption for Voriconazole, and to a lesser extent for fluconazole. The absorption of posaconazole and itraconazole increases with food intake. All of them have high tissue distribution with low plasma concentrations, especially low in the case of posaconazole and itraconazole. Posaconazole and itraconazole have high plasmatic protein binding and consequently both have a very low free fraction. Elimination of azole antifungals is through a metabolic pathway with CYP450 isoenzymes, and has a non linear pharmacokinetics with a high risk of interation with other drugs since azoles have the ability of CYP450 isoenzymes inhibition. Possibly the parameter that defines more precisely their efficacy is AUIC with an optimum value near 20, although cut-off values must be defined since some azoles may have difficulty to reach this value

The antler-like appendages of the primitive deer Dicrocerus elegans : morphology, growth cycle, ontogeny, and sexual dimorphism

Males and many females of the primitive deer Dicrocerus elegans from Sansan (Middle Miocene, France) bore antler-like appendages consisting of a simple-branched protoantler growing from a rather long pedicle and are decorated with ridges and furrows. The protoantler capacity to be rejected and subsequently re-grow is clearly evidenced by the presence of both pedicle and protoantler cast specimens. The youngest appendage is a long, laterally flattened shaft whose apex is usually forked with no appreciable limit between the pedicle and the protoantler. In females, the anterior and posterior appendage margins form a more acute angle than that of males, and are more parallel when viewed laterally. After the first casting, the protoantler base is larger than the pedicle top and a coronet-like structure appears developed only around the medial side. With successive castings, the pedicles become shorter and their section is more circular, while protoantlers become much bigger, and have much longer and more separated branches. Branches of females are shorter than those of males, especially the anterior one, and appear in a straight line, instead of being bent. In oldest appendages, the branches are shorter and more similar in size. Accessory branches and irregularities of this basic morphology are common. The separation between both sex morphotypes appears clearly evidenced by Discriminant and Principal Component Analyses. Histological features point to important differences with true antlers and suggest that casting could not occur annually. A core of spongy bone trabeculae is not developed. Once growth is completed, the mineralization progress from the core to the periphery and when the final 'velvet' protoantler becomes completely petrified, the tissues dies and the velvet-like skin is cleaned. A high degree of both wear and polish of the branch apices evidence the hard, bare, dead protoantler phase before casting. Due to the complete growth cycle and the presence of the coronet-like structure, Dicrocerus protoantlers and antlers seem to be homologous appendages. Histological differences could be related to differences in hormonal cycle regulation that can be caused by the fact that i) Dicrocerus inhabited a tropical environment, and ii) females also developed protoantlers. It should not be overlooked that true antlers appear several million years later in time than the development of protoantlers and other cranial appendages in ruminants, and coinciding with the Middle Miocene Climatic Transition.Tanto los machos como muchas de las hembras del ciervo primitivo Dicrocerus elegans de Sansan (Mioceno Medio, Francia) poseían apéndices craneales de tipo asta que consisten en una protoasta bifurcada y ornamentada con surcos y crestas que es sustentada por un pedículo moderadamente largo. La capacidad de la protoasta de ser expulsada y regenerada es evidente a partir de los ejemplares de desmogue y también por las diferencias histológicas existentes entre la protoasta y el pedículo.El primer apéndice consiste en una vara larga, comprimida lateralmente, y con el ápice bifurcado, sin que se observe ningun límite apreciable entre la protoasta y el pedículo. En las hembras, el ángulo que forman los margenes anterior y posterior del apéndice es más agudo que en los machos (los márgenes son más paralelos en vista lateral). Tras el primer desmogue, la base de la protoasta es más amplia que la sección distal del pedículo, y se desarrolla una estructura similar a la roseta en la parte medial. Con los sucesivos desmogues, el pedículo se acorta y su sección se hace más circular, mientras que la protoasta es cada vez más grande y las ramas son más largas y parten más separadas desde la base sin interposición de un tramo basal. En las hembras, las ramas son más cortas, especialmente la anterior, y su trazado es rectilíneo en vez de curvo como en los machos. En los ejemplares seniles, las ramas son más cortas y de longitud más similar entre ellas. Es frecuente la presencia de ramas accesorias, así como irregularidades de este patrón básico. Los análisis discriminantes y de componentes principales realizados muestran una clara separación entre los morfotipos atribuidos a machos y a hembras. Existen importantes diferencias histológicas con las verdaderas astas que sugieren que el desmogue podría no haber sido anual. Se confirma que no se desarrolla hueso esponjoso y que la mineralización del protoasta progresa centrífugamente desde el centro hasta la periferia. El desmogue tiene lugar una vez que los tejidos están completamente mineralizados (muertos). A diferencia de otras protoastas, el ciclo en Dicrocerus era completo dado que están documentadas tanto la fase de muda del terciopelo, como la de exposición del hueso desnudo antes del desmogue. Dadas las similitudes en el ciclo de crecimiento, y dado que la base de la protoasta presenta parcialmente una estructura similar a la roseta, las protoastas de Dicrocerus y las astas parecen ser apéndices homólogos. Las diferencias histológicas podrían estar relacionadas con diferencias en el ciclo hormonal que regulaba su crecimiento. Diferencias que podrían guardar relación con el hecho que i) Dicrocerus vivió en ambientes tropicales, ii) las hembras también poseían protoastas. Cabe resaltar que las verdaderas astas aparecieron varios millones de años más tarde de que surgieran las protoastas y otros apéndices craneales en Ruminantia, y en coincidencia con la transición climática del Mioceno Medio

Bioavailability of two oral fentanyl transmucosal formulations in healthy volunteers: an open-label, crossover, randomised study.

Introduction: Oral transmucosal fentanyl citrate (OTFC) was the first product specifically designed for the treatment of breakthrough pain. It is formulated as a sweetened lozenge on a plastic handle (stick) and it is self-administered by the patient, allowing the modulability or flexibility in dosing. Objectives: To prove bioequivalence of a test (T) OTFC product compared to the reference (R) formulation. Material and methods: Open-label, crossover, randomized, single-dose bioequivalence study in healthy volunteers, with two study periods and two sequences, with a washout period of at least 10 days. On each study day, subjects received 400 μg of fentanyl. They were instructed to rub the tablet gently against the buccal mucosa and not to suck on or chew it, and the investigators controlled each administration to ensure that it was consumed during 15 minutes. Given the high pharmacokinetic variability, a two-stage design was established and bioequivalence decision was based on 94.12% confidence intervals of Cmax and AUC0-t geometric means ratio. Results: 36 subjects completed the study according to the protocol. Mean Cmax were similar with both formulations (814.78 pg/ml for T and 781.83 pg/ml for R) and were attained at the same time (40 min. for T and 50 min. for R), and their bioavailability was also very close (AUC0-t: 3920.12 pg.h/ml for T and 3679.39 pg.h/ml for R). Bioequivalence was confirmed for the two primary parameters, Cmax and AUC0-t. No period or sequence effects were observed in any parameter. As bioequivalence was proved in the first phase of the study, it was not necessary to proceed to the second stage. The estimated intraindividual variability was 24.66% and 19.01%, respectively for T and R formulations. Both formulations were well tolerated; 15 mild adverse events were reported. Discussion: The test OTFC product is bioequivalent to the reference one and therefore interchangeable when used clinically. OTFC administration provides faster fentanyl absorption than enteral route and the rate of absorption can be modulated by the administration technique, providing a unique flexibility among all breakthrough pain treatments. The results showed a fast time to maximum concentrations (tmax), in accordance with those originally reported for the reference product, probably favoured by the strict administration technique. Proper patient education is essential to optimize the use of OTFC, as well-trained patients can take advantage of its flexibility to selfcontrolling pain relief

A multi-ootaxic assemblage from the Lower Cretaceous of the Cameros Basin (La Rioja; Northern Spain)

Here we describe the new fossil site of El Horcajo in the vicinity of Trevijano (La Rioja, Spain). It is located in the palustrine facies of the Enciso Group (Cameros Basin). This new locality has provided dozens of eggshell fragments, together with other vertebrate remains and charophyte fructifications, which allow dating of the locality as Valanginian-Hauterivian. Five ootaxa have being recognized: 1) the Spheroolithidae Guegoolithus turolensis; 2) a surprisingly thick Prismatoolithidae indet., with certain affinities to the oogenus Sankofa, that may represent a new oogenus and oospecies for this oofamily; 3) the Krokolithida

Valuing and Managing the Philippines’ Marine Resources toward a Prosperous Ocean-Based Blue Economy

The ocean-based “blue economy” is a significant part of the Philippine economy that has largely been taken for granted despite its enormous potential. It is of critical importance to a substantial segment of our population dependent on the seas and coastal resources for their livelihood and sustenance, appreciably enlarge the country’s wealth, and significantly contribute to its gross domestic product. This paper attempts to review the major issues concerning marine ecosystems in relation to the country’s pursuit of the blue economy. It discusses the economic and social activities in relation to the seas and coastal areas, and provides updated estimates of the real value of the country’s marine ecosystems’ goods and services. Based on primary and available secondary data, the marine ecosystems (excluding the continental shelf) can contribute a conservative monetary value of US$ 966.6 billion to the economy. In light of the risks and threats to the blue economy, the paper further discusses the country’s current national initiatives and involvement in regional collaborations toward ensuring its health and sustainable development. Given the Philippines’ vast largely untapped potential, a recommendation for the creation of a Department of Marine Resources, separate from the Department of Agriculture, seems in order

Nuevo hallazgo de restos de proboscídeo en depósitos fluviales afectados por procesos kársticos. Pleistoceno inferior de la Cuenca del Ebro, Zuera (Zaragoza).

Se da a conocer el hallazgo de una defensa incompleta de Elephantidae indet. en depósitos de gravas correspondientes a una terraza del río Gállego, próxima a la localidad de Zuera, de edad Pleistoceno inferior tardío. Los estudios estratigráficos realizados han permitido definir cuatro unidades denominadas de base a techo como U1 a U4 que en conjunto integran una sucesión de unos 35 m de espesor, situándose la defensa a techo de la unidad U1. El análisis tafonómico preliminar parece indicar que se trataría de un fósil reelaborado. Los depósitos se encuentran afectados por procesos kársticos en evaporitas que han dado lugar a estructuras de deformación con geometría sinforme laxa o tubular (delimitada por fallas). La existencia de estos procesos kársticos ha favorecido la conservación del resto fósil encontrado. A partial tusk of Elephantidae indet. was recently discovered in Early Pleistocene gravel deposits belonging to a terrace of the Gállego River, near to Zuera village. Stratigraphic studies have allowed four sedimentary units to be differentiated, named (from base to top) U1 to U4. The whole succession is 35 m thick; the tusk remains were collected at the top of unit U1. Preliminary report on the taphonomy suggests that this specimen could be a reworked fossil. Evaporite dissolution related with karst processes caused deformation structures in the overlying Quaternary deposits. Synform and tubular shapes (delimited by faults) were generated. Karstification favoured the preservation of the fossil remains

Critical appraisal of bilastine for the treatment of allergic rhinoconjunctivitis and urticaria

Bilastine is a second generation antihistamine indicated for the treatment of seasonal or perennial allergic rhinoconjunctivitis and chronic urticaria with a daily dose of 20 mg, in adults and children over 12 years of age. The efficacy of bilastine has been shown to be similar to that of the comparator drugs for the control of the nasal and nonnasal symptoms of allergic rhinoconjunctivitis, while also showing a subjective improvement in the quality of life and in overall clinical impression. For chronic urticaria the symptoms (itching and the development of papules) lessens from the second day of treatment onwards, in a similar way to other antihistamines used as comparators. Bilastine should not be administered at meal times to avoid interference with the absorption process. It is not distributed to the central nervous system, is scarcely metabolized, and elimination is through the kidneys and feces, with a 14-hour elimination half-life. It has no effect on cytochrome P450. During clinical development, bilastine was shown to be a drug that is adequately tolerated, with a similar effect to placebo with regard to drowsiness and changes in heart rate. In relation to its use, headaches were the most frequent adverse effect to be reported. No cardiotoxic effects have been observed, and the therapeutic dose does not alter the state of alertness

Posibles indicaciones del tratamiento de las enfermedades autoinmunes con tacrolimus

Tacrolimus is an immunosuppressive drug used most successfully as a primary drug to suppress the rejection of transplants. Tacrolimus may also be useful as a novel therapy for autoimmune disease. There are various reports in the bibliography about the use of tacrolimus in the treatment of some autoimmune diseases: inflammatory bowel disease, autoimmune hepatitis, cutaneous, neurologic, renal, endocrine or eye disease. In this review of more than 130 papers, we discuss the rationale for the use of tacrolimus in autoimmune disease and report the clinical experience with the drug in the management of a variety of autoimmune diseases. But, although there are a lot questions that require future research (dose, duration of treatment, when to begin tacrolimus treatment, how to monitor it, etc.), there is also wide experience with tacrolimus in the treatment of this type of disease