Monitorización y efectos secundarios de los inmunosupresores en el trasplante

ABSTRACT The success of organ transplants and their consideration as a clearly established treatment in some indications is due to the development of immunosuppressant drugs. While it was not the first of the drugs to be employed, the introduction of cyclosporin in the 1980s in immunosuppressant treatment made possible an increase in the number of transplants and the success of this practice. From then onwards, immunosuppression has been based on the use of a combination of drugs, initially cyclosporin, corticoids and azathioprine. In recent years new drugs have been introduced that have opened up the possibilities of treatment. But many pending questions remain, due to the toxicity associated with their use and the possibility of interaction with other drugs, which complicates their use and can compromise the prognoses of these patients. Calcineurin inhibitors and mTOR are the drugs involved with greater frequency in interactions with other drugs, which makes it necessary to anticipate this possibilit

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

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

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

Decolorization of Synthetic Textile Dyes by Fungal Endophytes Isolated from the Leaves of Philippine Mangrove (Avicennia marina)

Textile dyes in wastewater can be harmful pollutants when released into the environment without treatment. Biodegradation of textile dye effluents by different microbes, including fungi, has become popular as an alternative to physicochemical methods. The mangrove Avicennia marina is known to harbor endophytic fungi which have the potential to carry out dye degradation. Therefore, this study assessed the ability to decolorize synthetic dyes of endophytic fungi isolated from the leaves of A. marina. Of the nine fungal endophytes, Aspergillus niger, Syncephalastrum racemosum and Penicillium citrinum exhibited the highest mycelial growths in solid media, while all endophytes adsorbed Congo red. Through liquid decolorization assay, four isolates decolorized Congo red at greater than 89% decolorization rates. P. citrinum (55.45%), Mycelia sterilia (85.19%), A. flavus (44.91%) showed the highest decolorization rates of Methylene blue, Malachite green and Rhodamine B, respectively. The ligninolytic enzymes produced by the endophytic fungi, laccase exhibited the highest activity with values higher than the positive control

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

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

El libro blanco de la influencia responsable

Este libro tiene como objetivos promover la influencia responsable en las redes sociales, definir el ecosistema de la influencia, identificar las palancas que impulsan la confianza en torno al Influencer y mejorar la credibilidad, transparencia y eficacia del sector. El Libro Blanco tiene su origen en el conocimiento adquirido por iCmedia a raíz del desarrollo del Influencer Trust Label (ITL). El ITL es un proyecto cofinanciado por la Unión Europea, en el que iCmedia ha trabajado durante los últimos 18 meses. A través de él, iCmedia ha creado una Etiqueta de Confianza para los perfiles de las redes sociales de los Influencers. Esta etiqueta establece unos indicadores de responsabilidad y transparencia, que distinguen a aquellos influencers, marcas y agencias que actúan de modo responsable. Para realizar la Etiqueta de Confianza ITL se trabajó con influencers de toda España a través de focus groups. El Libro Blanco de la Influencia Responsable es el resultado de una gran conversación entre los stakeholders que forman el ecosistema de la influencia: usuarios y consumidores, influencers, marcas, agencias, medios de comunicación, plataformas sociales, instituciones y organizaciones, y reguladores. Entre todos, se dibujan y proponen los pasos a seguir para hacer real un entorno de influencia responsable. Para llevar a cabo este proyecto, se ha realizado una exhaustiva recogida de información a través de más 40 entrevistas en profundidad a los representantes más destacados de los agentes que componen el ecosistema de la influencia digital. Durante estas entrevistas, se ha analizado la situación actual, descrito los retos y palancas de cambio de la influencia responsable, y se han determinado las recomendaciones y pasos a seguir para crear un entorno de influencia responsable promovido por todas las partes implicadas. Este libro presenta los resultados de todo este trabajo de investigación. El Libro Blanco de la Influencia Responsable pretende impulsar en todos los usuarios, influencers y stakeholders del ecosistema de la influencia digital, el conocimiento del poder de influencia de los Influencers digitales y del impacto que tienen en la sociedad, especialmente en los menores. Todos juntos debemos caminar hacia la Influencia Responsable

Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.

PURPOSE: To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity. PATIENTS AND METHODS: Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals. RESULTS: Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment. CONCLUSION: Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy