[Aflibercept. An approach to pharmacology]. / Aflibercept. Una aproximación a la farmacología.

Aflibercept is a fusion protein whose chemical structure combines the constant fraction of any IgG with a variable fraction constructed with fundamental parts of VEGF receptors. Consequently, it is able to bind to various VEGF as well as to placental growth factor (PIGF), which has been related to a possible synergistic effect in efficacy. The affinity of this drug is higher than that of ranibizumab and bevacizumab. Moreover, it has an intraocular antiinflammatory effect. Intravitreal administration leads to the presence of traces of the drug in plasma but the concentrations are so reduced that the presence of systemic adverse effects, including arterial hypertension, is practically nil. Because of its prolonged intraocular elimination half-life and high affinity, the drug can be administered in convenient regimens, since, after an initial monthly injection for the first three doses, the interval between injections is increased to one every two months and, after the first 12 months, the dosing will depend on the visual and anatomical results.

Aflibercept. Una aproximación a la farmacología / Aflibercept. An approach to pharmacology

Aflibercept es una proteina de fusion que combina en su estructura quimica, la fraccion constante de cualquier IgG con una fraccion variable construida con partes fundamentales de los receptores del factor de crecimiento del endotelio vascular, por ello es capaz de fijar a diversas isoformas del factor de crecimiento del endotelio vascular y tambien al factor de crecimiento placentario, lo que se ha puesto en relacion con un posible efecto sinergico en la eficacia. La afinidad es mayor que la que presentan ranibizumab y bevacizumab. Ademas produce un efecto antiinflamatorio intraocular. La administracion por via intravitrea cursa con la presencia de trazos del farmaco en el plasma del paciente; de hecho, las concentraciones son tan reducidas que la presencia de efectos adversos sistemicos, incluida la hipertension arterial, es practicamente nula. Una semivida de eliminacion intraocular prolongada unida a la afinidad elevada supone que sea posible la utilizacion en pautas posologicas comodas, ya que tras una inyeccion mensual para las 3 primeras dosis se aumenta el intervalo a una inyeccion cada 2 meses, que tras los primeros 12 meses puede vincularse a los resultados visuales y anatómicos (AU)

Aflibercept is a fusion protein whose chemical structure combines the constant fraction of any IgG with a variable fraction constructed with fundamental parts of VEGF receptors. Consequently, it is able to bind to various VEGF as well as to placental growth factor (PIGF), which has been related to a possible synergistic effect in efficacy. The affinity of this drug is higher than that of ranibizumab and bevacizumab. Moreover, it has an intraocular antiinflammatory effect. Intravitreal administration leads to the presence of traces of the drug in plasma but the concentrations are so reduced that the presence of systemic adverse effects, including arterial hypertension, is practically nil. Because of its prolonged intraocular elimination half-life and high affinity, the drug can be administered in convenient regimens, since, after an initial monthly injection for the first three doses, the interval between injections is increased to one every two months and, after the first 12 months, the dosing will depend on the visual and anatomical results (AU)

Monoclonal antibodies: pharmacokinetics as a basis for new dosage regimens?

Complete monoclonal IgG antibodies which are in use in clinical practice share some pharmacological properties resulting in high concentrations in plasma. This fact is reflected in their low volumes of distribution, which can also be correlated with a high molecular weight and water solubility. This feature allows a novel approach to be applied to the dosing schedule for this group of drugs with fixed doses being used instead of the initially developed weight- or body surface-adjusted dosing schedules. In addition, the development of a new formulation containing hyaluronidase allows a subcutaneous route of administration to be used, because hyaluronidase creates a space in the subcutaneous tissue that helps antibody absorption. This method requires higher doses, but has allowed testing the feasibility of administering a fixed dose, with no individual dose adjustments based on weight or body surface. Moreover, loading doses are not needed, because the first dose results, within 3 weeks, in minimum concentrations that are higher than effective concentrations.

Oral availability of bilastine.

BACKGROUND AND OBJECTIVE: Bilastine (Bilaxten™) is a novel non-sedating H1 receptor antagonist (antihistamine) developed in the dosage form of oral tablets and indicated for the treatment of allergic rhinitis (seasonal and perennial) and urticaria. Several clinical trials have been performed in order to determine the efficacy and safety of bilastine. The aim of this trial was to study the absolute oral bioavailability of bilastine in humans. METHODS: Twelve male and female adults were recruited into a single centre for a randomized, single-dose, open-label, controlled two-arm crossover study with a minimum 14-day washout period between the two single doses. Two single doses of bilastine were administered: a 20-mg oral tablet and a 10-mg intravenous formulation. Blood and urine samples were collected between 0 and 72 h post each administration. The clinical trial was carried out under quality assurance and quality control systems with standard operating procedures to ensure that the study was conducted and data generated in compliance with the protocol, Good Clinical Practice standards, International Conference on Harmonisation and other applicable regulations. RESULTS: Oral bioavailability of bilastine was 60.67 % with a 90 % parametric confidence interval of 53.79-67.56. The maximum bilastine concentration was measured 1.31 h after oral administration. Pharmacokinetic parameters were similar to those observed in previous studies. Tolerance to treatment was good, with no adverse events related to study medication. CONCLUSION: The absorption of bilastine after oral administration to healthy subjects was rapid. The absolute oral bioavailability was moderate.

A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma.

The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10¹° to 2 × 10¹² viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10¹² vp per patient.

Pharmacokinetic/pharmacodynamic serum and urine profile of cefditoren following single-dose and multiple twice- and thrice-daily regimens in healthy volunteers: a phase I study

El objetivo del estudio fue valorar la farmacocinética, la farmacodinámica y la tolerabilidad digestiva del cefditoreno pivoxilo en 20 voluntarios varones adultos sanos tras su administración cada 8 horas. Durante el primer día la mitad de ellos recibieron una dosis única de 200 mg y la otra mitad 400 mg. Tras un periodo de lavado de ocho días, ocho voluntarios recibieron 400 mg cada 12 horas, otros ocho 400 mg cada 8 horas y cuatro placebo durante 10 días, siguiendo un diseño aleatorizado y doble ciego. La medicación se tomó 30 minutos después de las comidas. Se recogieron muestras de sangre y orina en los días 1, 9, 14 y 19. Se preguntó a los voluntarios si habían notado algún trastorno digestivo, sobre todo en sus hábitos intestinales, náuseas, vómitos o dolor abdominal. El valor medio de la concentración máxima de cefditoreno (Cmax) fue 3,77±0,66 mg/l y se alcanzó tras 1,5 a 3 horas con la administración tres veces al día. En el régimen de administración cada 12 horas la Cmax fue 3,27±0,64 mg/l. El tiempo medio por encima de la CMI calculado a partir de los datos derivados de cada perfil farmacocinético superó siempre el 40%, tanto cuando se administraba el fármaco cada 12 horas como cada 8 horas. La semivida del cefditoreno fue 1,19±0,2 horas y 1,36±0,2 horas para la administración cada 12 y cada 8 horas, respectivamente. La máxima concentración de cefditoreno en la orina se alcanzó entre 2 y 4 horas después de la administración, con un valor medio de 154,53 mg/l cuando se administraba cada 12 horas y 186,59 mg/l cuando se hacía cada 8 horas. No se encontraron diferencias en la incidencia de efectos adversos digestivos entre los grupos. Estos datos demuestran que se puede administrar 400 mg cada 8 horas, porque esta dosis se tolera bien y aumenta la probabilidad de tener éxito cuando la CMI de la bacteria causante se encuentra cerca del punto de corte de sensibilidad. Las elevadas concentraciones de fármaco activo en la orina permiten considerar al cefditoreno como un fármaco útil en el tratamiento de las infecciones de vías urinarias no complicadas

The objectives of this randomized, double-blind study were to evaluate the pharmacokinetics, and the pharmacodynamic and gastrointestinal (GI) tolerance of cefditoren pivoxil in healthy adult male volunteers when it is administered three times a day. Twenty healthy volunteers were included in the study. On day 1, 10 subjects received a 200-mg single dose of cefditoren pivoxil and 10 received a 400-mg dose. After a washout period of 8 days, eight subjects received cefditoren pivoxil 400 mg b.i.d., eight received 400 mg t.i.d., and four received placebo for 10 days. Medication was taken 30 min after meals. Blood and urine collections were carried out on days 1, 9, 14 and 19. Volunteers were asked about any GI change, especially about bowel habits, nausea, vomiting and abdominal pain. The maximum cefditoren concentration (Cmax) had a mean value of 3.77±0.66 mg/l, and was reached between 1.5 and 3 h in the thrice-daily administration. In the twice-daily regimen, the Cmax was 3.27±0.64 mg/l. The mean time above breakpoint minumum inhibitory concentration (MIC), calculated with data from each pharmacokinetic profile, was always above 40%, in both the twice- and thrice-daily regimens. The half-life of cefditoren was 1.19±0.2 h and 1.36±0.2 h in the twice-daily and thrice-daily regimens, respectively. The Cmax of cefditoren in urine was reached between 2 and 4 h postadministration, with a mean value of 154.53 mg/l in the twice-daily regimen, and 186.59 mg/l in the thrice-daily administration. There were no differences between the groups in the incidence of GI adverse events. The present data show that the administration of cefditoren pivoxil 400 mg t.i.d. is possible because it is well tolerated, and it increases the probability of success when the MIC of the causative bacteria is close to the susceptibility breakpoint. The high concentrations of active drug in the urine enable cefditoren to be considered as a useful candidate for the treatment of uncomplicated urinary tract infections (UTIs)

Detection and incidence of drug-induced agranulocytosis in hospital: a prospective analysis from laboratory signals.

AIMS: Our objectives were to assess the detection and incidence of drug-induced agranulocytosis in two university hospitals using hematology laboratory data. METHODS: A prospective study was undertaken at Toulouse University Hospital (France) and Navarra University Hospital (Spain) for 1 year (from 1 May 2004 to 30 April 2005). Using a computerized process and hematology laboratory data, all neutrophil counts with a value less than 500/mm(3) were registered, allowing identification of inpatients suffering from agranulocytosis during the period of the study. Medical records of all selected patients were then consulted. Cytostatic drugs were excluded from this study. RESULTS: During the period of the study, 225,659 neutrophil counts were performed in both hospitals, of which 2,835 (1.26%) had a neutrophil count less than 500/mm(3), corresponding to 739 patients. Seventeen patients were excluded because of lack of data, and 20 cases of infants younger than 3 months were excluded. Among the remaining patients (n = 702), 23 cases of drug-induced agranulocytosis (excluding cytostatic drugs) were suspected. All cases were classified as "serious" since they led to death in 2 cases, hospitalization or prolongation of hospitalization in 19 cases and threatening of vital prognosis in 2 cases. Withdrawal of suspected drugs was done in all cases with regression of neutropenia in 21 cases. According to hospitalization data, the annual incidence of drug-induced agranulocytosis was 1.62 (1.0-2.6) per 10,000 inpatients in Toulouse University hospital (based on 534 cases) and 3.24 (0.9-8.3) per 10,000 inpatients in Navarra University Hospital (based on 168 cases). The involved drugs were mainly antibacterial (30.4%), immunosuppressive (17.4%), antithyroid (13.0%), antiplatelet (8.7%) and nonsteroidal anti-inflammatory (8.7%) ones. Only seven cases from Toulouse University Hospital were spontaneously reported by physicians during the same period. Thus, the underreporting coefficient (U) was 2.71 (63.2%) in France. CONCLUSION: Our survey allowed us to identify the suspected drug-induced agranulocytosis through a prospective study in a large sample of inpatients using only laboratory data analysis. We also note an important underreporting rate of this serious adverse drug reaction (ADR) to the official French pharmacovigilance system. Laboratory data analysis could be used for identifying serious ADRs.

[Monitoring and secondary effects of immunosuppressants in the transplant]. / Monitorización y efectos secundarios de los inmunosupresores en el trasplante.

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 possibility when the concomitant medication is changed.

Monitorización y efectos secundarios de los inmunosupresores en el trasplante / Monitoring and secondary effects of immunosuppressants in the transplant

El éxito del trasplante de órganos y su consideración como un tratamiento claramente establecido en algunas indicaciones se debe al desarrollo de fármacos inmunosupresores. Aunque no fue el primero de los fármacos utilizados, la introducción de la ciclosporina en los años 80 en el tratamiento inmunosupresor permitió el incremento del número de trasplantes y el éxito de esta práctica. Desde ese momento, la inmunosupresión se ha basado en la utilización de una combinación de fármacos, inicialmente ciclosporina, corticoides y azatioprina. En los últimos años se han introducido nuevos fármacos que han abierto las posibilidades de tratamiento. Pero todavía quedan algunas cuestiones pendientes, debido a la toxicidad asociada a su uso y a la posibilidad de interacciones con otros fármacos, lo cual complica su manejo y puede comprometer el pronóstico de estos enfermos. Inhibidores de la calcineurina y de la mTOR son los fármacos implicados con mayor frecuencia en interacciones con otros fármacos, lo cual obliga a anticiparse a esta posibilidad cuando se cambia la medicación concomitante

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 possibility when the concomitant medication is changed

Nuevas perspectivas del tratamiento inmunosupresor en el trasplante de órganos / New perspectives in immunosuppresion

No disponible

No disponible

[Treatment with tacrolimus in autoimmune diseases]. / 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.

Relationship between pharmacokinetics and pharmacodynamics of beta-lactams and outcome.

The in-vitro susceptibility of an organism and the pharmacokinetics of an antimicrobial agent are two basic factors on which the choice of standardised treatment regimens is based. However, the inter-individual variability of these factors, which modifies the exposure of bacteria to an antibiotic in terms of time and quantity, is not usually taken into account. In 87 patients treated with beta-lactams (ceftriaxone, cefepime or piperacillin), the probability of failure was greater when the infectious process was located in tissues with barriers to the distribution of beta-lactams. Mean MICs of piperacillin and cefepime, but not ceftriaxone, were below the breakpoints in cases of both recovery and failure, but organisms isolated from patients with a poor outcome had higher MICs. Therefore, the use of breakpoints to determine the susceptibility of microorganisms was not satisfactory in predicting the outcome for a large number of patients. If MICs are determined and plasma concentrations are monitored, dosages can be adjusted according to these parameters, thereby allowing antibiotic treatment to be individualised.

Clinical relevance of sirolimus drug interactions in transplant patients.

Sirolimus, a new immunosuppressant drug; is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of the P-glycoprotein drug efflux pump. The CYP3A4/P-glycoprotein system is mainly localized in the liver and intestine. It is responsible for the severe first pass metabolism of sirolimus with a low bioavailability. Drugs like voriconazole, itraconazole, fluconazole, and erytrhomycin may decrease the metabolic activity of this enzymatic system. This report documents in five patients that coadministration of these antimicrobials with sirolimus increases the blood concentrations of the immunosuppressant. The dose-normalized trough blood concentration showed a mean increase of sevenfold with the coadministration of these drugs. It is essential to monitor the blood sirolimus concentrations and to adjust the sirolimus doses before and after coadministration of these drugs.

A propósito de los estudios con fármacos tras la comercialización, ¿obligaciones o prohibiciones? / On studies with medicines after commercialisation, obligations or prohibitions?

No disponible

Development of a chromatographic method for the determination of saquinavir in plasma samples of HIV patients.

A simple, sensitive and reproducible high-performance liquid chromatographic method for detecting and quantifying saquinavir in human plasma is described. Verapamil was used as internal standard. The method employes a single liquid-liquid extraction step with tert-butil methyl ether followed by chromatography on a Lichrospher 60 Select B C8 reversed-phase column. Ultraviolet detection was used to identify the compounds of interest. The quantitation limit of saquinavir was 1 ng/mL and only 0.5 mL of plasma sample was required for the determination. The average saquinavir recoveries over a concentration range of 2.5-500 ng/mL ranged from 86 to 95%. Precision and accuracy did not exceed 5%.