RESUMEN
We hypothesized that pazopanib is an inhibitor of cisplatin renal transporters OCT2, MATE1 and MATE2-K based on previous studies demonstrating an interaction between tyrosine kinase inhibitors and these transporters. Because several combinations of targeted therapies and cytotoxics are currently in development for cancer treatment, such an interaction is worth investigating. Experiments on HEK293 cells stably transfected to express OCT2, MATE1, MATE2-K or an empty vector (EV) were conducted. The inhibitory effect of pazopanib on these transporters was measured using the uptake of fluorescent substrate ASP+ and cisplatin in the different cell lines. The effect of pazopanib on cisplatin-induced cytotoxicity was also evaluated. A decrease of ASP+ uptake was observed in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines after addition of pazopanib at increasing concentrations. Pazopanib inhibited cisplatin specific uptake in OCT2-HEK, MATE1-HEK and MATE2K-HEK lines. Cytotoxicity experiments showed that co-incubation of cisplatin with pazopanib multiplied up to 2.7, 2.4 and 1.6 times the EC50 values of cisplatin in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines respectively, reaching about the same values as in EV-HEK cells. To conclude, pazopanib inhibits OCT2, MATE1 and MATE2-K, which are involved in cisplatin secretion into urine. The combination of these two drugs may lead to an interaction and increase the cisplatin-induced systemic toxicity. Given the wide variability of plasma pazopanib concentrations observed in vivo, the interaction may occur in a clinical setting, particularly in overexposed patients. The existence of a drug-drug interaction should be investigated when pazopanib is associated with a substrate of these transporters.
Asunto(s)
Inhibidores de la Angiogénesis/toxicidad , Cisplatino/toxicidad , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico/antagonistas & inhibidores , Pirimidinas/toxicidad , Sulfonamidas/toxicidad , Supervivencia Celular/efectos de los fármacos , Cisplatino/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Células HEK293 , Humanos , Indazoles , Cinética , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/genética , Transportador 2 de Cátion Orgánico/metabolismo , Compuestos de Piridinio/metabolismo , Eliminación Renal/efectos de los fármacos , TransfecciónRESUMEN
The annual number and incidence of congenital rubella syndrome (CRS) in Poland was evaluated by means of a methematical model and on the basis of serological studies. In its principles this model describes the infectious kinetics of rubella by the formula y = 1--e-at, where "y" is the rate of immune persons, "a" is a parameter representing the transfer of susceptibles to immunes and "t" is age. The calculated incidence of congenital rubella syndrome resulted in average values of 0.15 to 0.38%, i.e. 15 to 38 CRS cases among 100,000 children born to mothers primarily infected by rubella virus during the first trimester of pregnancy.
Asunto(s)
Síndrome de Rubéola Congénita/epidemiología , Rubéola (Sarampión Alemán)/epidemiología , Métodos Epidemiológicos , Femenino , Humanos , Recién Nacido , Modelos Teóricos , Polonia , EmbarazoAsunto(s)
Anticuerpos Antivirales/análisis , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/inmunología , Herpes Simple/diagnóstico , Simplexvirus/inmunología , Adolescente , Adulto , Niño , Preescolar , Infecciones por Citomegalovirus/inmunología , Femenino , Herpes Simple/inmunología , Humanos , Lactante , Recién Nacido , PoloniaRESUMEN
Out of 1670 pregnant women contacts examined for antibodies to rubella virus, recent rubella infection was confirmed in 5.1% of subjects, 2.2% of which were symptomatic and 2.9% asymptomatic; 89.9% of tested women were seropositive. These results closely resembled those, obtained in serological surveys, carried out in Poland several times in the years 1969-82. Rubella antibodies were found in over 90% of women in childbearing age, with HI antibody geometric mean titre (GMT) 58.7-84.3 (depending on the epidemiologic situation). Especially high GMT--of 122--was detected in women of the 30-34 year age group after the rubella epidemic in 1980/81, which showed the highest rubella morbidity of 5-9 year-old children. Reactogenicity and immune response in 10-13 year-old vaccinated girls were investigated. Seroconversion among seronegatives, among subjects with low antibody level (less than 1:20) and among seropositives with antibody titres 40 or higher before vaccination occurred in 99.8%, 60% and 12.8% of cases, respectively. HI antibody GMT after immunization was 132.6-135, similar to GMT induced by naturally acquired infection in the women of 30-34 year age group after the rubella epidemic. The difference of GMT in vaccinated girls with joint symptoms (152) and without postvaccinal reactions (124) was statistically significant. Practical conclusions for rubella diagnostic and vaccination programmes based on the analogies and differences of antirubella immunity in infected pregnant women, in naturally infected children and adults, and in vaccinated subjects are discussed.
Asunto(s)
Anticuerpos Antivirales/biosíntesis , Vacuna contra la Rubéola/inmunología , Virus de la Rubéola/inmunología , Rubéola (Sarampión Alemán)/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Inmunidad Activa , Inmunoglobulina M/biosíntesis , Lactante , Recién Nacido , Polonia , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Rubéola (Sarampión Alemán)/epidemiologíaAsunto(s)
Infecciones por Coxsackievirus/diagnóstico , Infecciones por Citomegalovirus/diagnóstico , Encefalitis/etiología , Infecciones por Herpesviridae/diagnóstico , Meningitis Viral/etiología , Adolescente , Niño , Preescolar , Diagnóstico Diferencial , Enterovirus , Femenino , Herpesvirus Humano 4 , Humanos , Lactante , Recién Nacido , MasculinoAsunto(s)
Anticuerpos Antivirales/análisis , Unidades de Hemodiálisis en Hospital , Unidades Hospitalarias , Fallo Renal Crónico/inmunología , Personal de Hospital , Diálisis Renal , Simplexvirus/inmunología , Adolescente , Adulto , Portador Sano/inmunología , Femenino , Herpes Simple/inmunología , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Factores de Tiempo , Recursos HumanosRESUMEN
Haemolytic activity of complement (CH50) and occurrence of circulating immune, complexes (CIC) were studied in serum samples from children with mumps meningitis taken at regular intervals. The decrease of CH50 was observed in 46 out of 77 samples (60%) in the Ist examination, between 1-6th day from the appearance of symptoms, in 43/67 samples (64%) in the IInd examination, between 12--16th day of disease, and in 7/22 samples (32%) in the IIIrd examination, between 12--14th month of observation since the appearance of symptoms. Typical changes of complement level during the disease were of such profile that the most pronounced decrease was in the Ist and IInd examination with the normalization in the IIIrd examination. The presence of CIC was found in 21%, 15% and 14% of samples in the Ist, IInd, and IIIrd examination respectively. Serum sample form the child on 5th day of disease, with high concentration of CIC (482 micrograms/ml), was subjected to sepharose 6B gel filtration on the calibrated column. The molecular weight of thus analyzed immune complexes was as follows: 2.5 X 10(6) and 5.0 X 10(5) daltons. CIC contained anti-mumps antibodies, determined by Elisa, in IgG, IgA and IgM classes.