Anfotericina B forma liposómica: un perfil farmacocinético exclusivo. Una historia inacabada.

Amphotericin B in its lipid formulation continues to be the reference drug in the treatment of systemic fungal infections despite the time elapse since the development of this compound. The absence of fungal resistance, pharmacokinetics, and the better tolerability profile as compared with the remaining formulations of amphotericin B are sufficient reasons to justify its prominent therapeutic role. The liposome containing liposomal amphotericin B is very stable in relation to the presence of cholesterol and phospholipids are not thermolabile, so that free amphotericin B is almost inexistent (<1%), which explains the reduced incidence of effects related to the drug administration, and a reduction in the incidence of nephrotoxicity (half than that with amphotericin B lipid complex) and that even in some studies at doses of 1 mg/kg has been shown to be negligible. This profile explains the very high plasma drug concentrations and the reduced distribution volume and clearance, with a very prolonged elimination half-life. There are evidences showing that the liposome through amphotericin B is capable of binding to ergosterol present in the fungal membrane and only at this moment would be the antifungal released to exert its pharmacological effects

Infecciones más comunes en el paciente trasplantado

Organ transplantation has become one of the most important areas of medical research and, at present, is still the only therapeutical tool for several diseases. However, there are a number of factors related to transplantation, like immunosuppression and prolonged neutropenia that affect the incidence of infection. These infections are somehow peculiar to trasplant recipients. In fact, there are infectious diseases that only occur in immunodepression situations and, moreover, clinical expression of these infectious diseases can be quite different from that in immunocompetent patients. Besides these aspects, some infections, due to the high prevalence described, must be considered for prevention strategies because they continue to be a principal cause of morbidity and mortality, either due to direct effects or to their implication in the pathogenesis of rejection. These strategies commence before trasplantation by active immunization through vaccine administration to the patient and to people in the milieu and continue after trasplantation with prophylaxis or pre-emptive therapy. The importance of infectious diseases in the evolution and prognosis of trasplant recipients gives a special meaning to the understanding of associated infections, their clinical expression and ways of prevention and treatment

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

Arte, arquitectura y emblemática en tres certámenes poéticos zaragozanos del Siglo de Oro

Por su propia naturaleza, el certamen poético presenta un marcado carácter literario que, sin embargo, no excluye su dimensión artística, sobre todo en la categoría dedicada a la composición de jeroglíficos. Así queda de manifiesto en sendos certámenes zaragozanos celebrados en 1614 y 1628 en honor a la beata Teresa de Jesús y a la Virgen del Pilar, que contaron con la participación del tracista descalzo fray Alberto de la Madre de Dios y del pintor Jusepe Martínez respectivamente. A ello se suma el ejemplo de la arquitectura al servicio del jeroglífico, con la Cruz del Coso como protagonista de una empresa para el recién nombrado inquisidor general fray Luis Aliaga en el certamen poético organizado en su honor en 1619. Este trabajo propone la reconstrucción material de los jeroglíficos zaragozanos, a través de los cuales estableceremos las conexiones entre arte, poesía y emblemática tan frecuentes en el marco de la fiesta barroca del Siglo de Oro

Arte, arquitectura y emblemática en tres certámenes poéticos zaragozanos del Siglo de Oro

Por su propia naturaleza, el certamen poético presenta un marcado carácter literario que, sin embargo, no excluye su dimensión artística, sobre todo en la categoría dedicada a la compo-sición de jeroglíficos. Así queda de manifiesto en sendos certámenes zaragozanos celebrados en 1614 y 1628 en honor a la beata Teresa de Jesús y a la Virgen del Pilar, que contaron con la participación del tracista descalzo fray Alberto de la Madre de Dios y del pintor Jusepe Martínez respectivamente. A ello se suma el ejemplo de la arquitectura al servicio del jeroglífico, con la Cruz del Coso como protagonista de una empresa para el recién nombrado inquisidor general fray Luis Aliaga en el certamen poético organizado en su honor en 1619. Este trabajo propone la reconstrucción material de los jeroglíficos zaragozanos, a través de los cuales estableceremos las conexiones entre arte, poesía y emblemática tan frecuentes en el marco de la fiesta barroca del Siglo de Oro.By its very nature, the poetic contest presents a marked literary character which, however, does not exclude its atistic dimension, mainly in the category of hieroglyphs. We can verify this in both Zaragoza contests held in 1614 and 1628 in honor of Blessed Teresa de Jesus and Virgin of Pilar, which counted with the participation of the Barefoot Carmelite architect fray Alberto de la Madre de Dios and the painter Jusepe Martinez respectively. To this we can add the example of architecture in the service of the hieroglyphic, as shows the Cross of the Coso, protagonist of an imprese for the newly appointed General Inquisitor fray Luis Aliaga in the poetic contest organized in his honor in 1619. This paper proposes the material reconstruction of the Zaragoza hieroglyphs, through which we’ll establish the relationship among Art, Poetry and Emblematic Literature, so frequent in the context of Spanish Golden Age festivities

Monitoring of Trough Plasma Ganciclovir Levels and Peripheral Blood Cytomegalovirus (CMV)-Specific CD8+ T Cells To Predict CMV DNAemia Clearance in Preemptively Treated Allogeneic Stem Cell Transplant Recipients

It is uncertain whether monitoring plasma ganciclovir (GCV) levels is useful in predicting cytomegalovirus (CMV) DNAemia clearance in preemptively treated allogeneic stem cell transplant recipients. In this observational study, including 13 episodes of CMV DNAemia treated with intravenous (i.v.) GCV or oral valganciclovir, we showed that monitoring trough plasma GCV levels does not reliably predict response to therapy. Rather, immunological monitoring (pp65 and immediate-early [IE]-1-specific gamma interferon [IFN-γ]-producing CD8+ T cells) appeared to perform better for this purpose

Levofloxacino. Experiencia clínica en tratamientos de larga duración de infecciones osteoarticulares

Se ha realizado un estudio con el fin de evaluar la eficacia y la tolerancia de la administración de larga duración de levofloxacino en el tratamiento de infecciones osteoarticulares. Se incluyeron 50 pacientes con una previsión inicial de realizar tratamiento antibiótico de duración superior a cuatro semanas, durante los años 1999-2001. El 46% de los pacientes eran varones y recibieron tratamiento con levofloxacino durante una media de 122,8 días. En el 83,7% de los pacientes evaluables (41/49 pacientes) la evolución fue satisfac- toria, por la desaparición o mejoría de la infección. Se realizaron controles médicos y analíticos seriados, sin objetivarse en ellos alte- raciones significativas. Cinco de los pacientes estudiados presenta- ron un total de 7 efectos adversos: molestias digestivas (3), micosis oral (1), petequias (1), parestesias (1) y erupción pruriginosa(1). En tres de ellos se suspendió el tratamiento por este motivo. Se concluye que levofloxacino es un fármaco eficaz y bien tolerado, por ello puede ser utilizado en el tratamiento de infecciones que requieran terapia prolongada.We evaluated the efficacy and safety profile of the long-term administration of levofloxacin in osteoarticular infections. For this purpose, 50 patients were included during the years 1999 to 2001 on an initial estimation to be under treatment with this antibiotic for at least 4 weeks. Forty six percent (46%) of patients were male and received treatment during a mean-time of 122.8 days. In forty one of a total of forty nine evaluable patients (83.7%) outcome was considered satisfactory with a total recovery or improvement of disease. Clinical and analytical series of examinations were performed, with no significant abnormalities being observed. Five (5) patients presented a total of 7 adverse events: gastrointestinal intolerance (3), oral mycosis (1), petechia (1), parestesia (1) and pruriginous rash(1). Only in three cases interruption of therapy was considered necessary. In conclusion, levofloxacin presents an adequate efficacy and is a well-tolerated therapy; both characteristics make it an appropriate treatment for those infections that require long-term therapy

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

Estudio de la eficacia antihipertensiva y tolerancia del bopindolol (LT 31-200) en pacientes hipertensos

Se ha realizado un estudio abierto con dosis crecientes de bopindolol, beta-bloqueante no selectivo de vida media larga, en pacientes con hipertensión arterial leve y moderada para valorar la eficacia y seguridad del tratamiento a corto y largo plazo. Se incluyeron 20 pacientes (12 mujeres y 8 varones) con edades comprendidas entre 36 y 62 años (x ± SD 51,6 ± 7,6) cuyas TA fueron superiores a 160 mm de Hg para la sistólica y entre 90 y 125 mm de Hg para la diastólica (x ± SD 165 ± 7,2 y 102,6 ± 6,7 respectivamente). Todos los pacientes fueron informados de las características del estudio y dieron su consentimiento por escrito para participar en el mismo. Tras la anamnesis y exploración física correspondientes se realizaron pruebas analíticas y complementarias con la finalidad de descartar patología asociada. Diecinueve de los veinte pacientes (95 %) respondieron satisfactoriamente tras 20 semanas de tratamiento con bopindolol oral una vez al día observándose diferencias estadísticamente significativas (p ≤ 0,001) a la 4.ª semana de tratamiento respecto a las cifras tensionales del período placebo (TA sistólica media 141,2 ± 17, TA diastólica media 87,22 ± 6,5). Resultados similares fueron obtenidos respecto a la frecuencia cardiaca. Las cifras de HDL-colesterol aumentaron significativamente (p ≤ 0,001) al igual que el cociente HDL-colesterol/colesterol total. No hubo variaciones importantes respecto al resto de parámetros estudiados. La tolerancia clínica fue buena en general, aunque algunos pacientes refirieron cefalea, somnolencia y náuseas, de intensidad moderada que no precisaron suspender el tratamiento