RESUMEN

OBJECTIVES: To provide detailed data on the tolerability and safety of octagam® 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. METHODS: A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level. RESULTS: In this analysis of 112 patients receiving octagam® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. DISCUSSION: In this subgroup analysis of patients who received octagam® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. CONCLUSIONS: Routine clinical use of octagam® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Inmunoglobulinas Intravenosas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoglobulinas Intravenosas/farmacología , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

OBJECTIVE: To evaluate the tolerability and safety of Octagam® 5% and 10% across all indications, ages, and treatment regimens, using data from four non-interventional post-authorization safety studies (PASS); this analysis was performed following changes in the preparation of raw material used to manufacture Octagam. METHODS: All four studies included in- and out-patients prescribed Octagam for treatment of their medical condition. Physicians used case report forms to document baseline demographics, Octagam treatment details, and data on the efficacy of Octagam, and recorded all adverse drug reactions (ADRs) and other safety data. RESULTS: Altogether 21,780 infusions of Octagam in 2,397 patients were included in our analysis. The most frequent indication for Octagam was secondary immunodeficiencies (SID; n = 1,368, 11,348 infusions), followed by primary immunodeficiencies (PID; n = 363; 3,923 infusions). During the individual patient observation, 83% of SID and 67% of PID patients were free of any infection. In up to 85% of all investigator assessments, Octagam was rated to have a favorable effect. In autoimmune diseases, investigators assessed Octagam as being beneficial in 70% (immune thrombocytopenia) up to 100% (Guillain-Barré syndrome), depending on the indication. The majority of patients (92%) tolerated Octagam treatment without any ADR. The overall incidence of reported ADRs was 1.0% for all infusions. The majority of ADRs were considered non-serious (93%) and mild or moderate (87%) in severity. No unexpected ADR signal was detected. CONCLUSIONS: This analysis demonstrates that the changes in the preparation of raw material used to manufacture Octagam did not affect the safety profile of Octagam® 5% and 10%.
 *At the time of study realization.

Asunto(s)

Inmunoglobulinas Intravenosas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/terapia , Niño , Preescolar , Femenino , Síndrome de Guillain-Barré/terapia , Humanos , Inmunoglobulinas/deficiencia , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Trombocitopenia/terapia , Resultado del Tratamiento , Adulto Joven

RESUMEN

PURPOSE: Following the approval of Octagam in 1995, an open prospective observational cohort study has been initiated to observe the tolerability of the intravenous immunoglobulin Octagam. This study aimed to evaluate the long-term safety profile of Octagam in daily use in the treatment of various primary (PID) and secondary (SID) immunodeficiencies and autoimmune diseases (AID). METHODS: Within a time period of 10 years, data were collected in 310 study sites. The treating physicians documented patient characteristics, treatment parameters and the occurrence of an adverse drug reaction (ADR) by using detailed case record forms (CRF). RESULTS: A total of 6357 patients of all ages received 92 958 infusions of Octagam. ADR occurred in 4.2% of the patients and in 0.35% of all infusions. Most of them (94.8%) were classified as nonserious, the majority (90.2%) were of mild or moderate intensity. The ADR frequency differed slightly between the indication groups, for example in PID patients ADR occurred in 8.3% of patients and 0.5% of infusions, in SID patients in 5.0% of patients and 0.62% of infusions. Rigors were reported most frequently, followed by fever, headache, nausea and flush. The ADR symptoms differed between the indication groups, rigors were predominantly described in SID patients, headache in PID and AID patients including idiopathic thrombocytopenic purpura (ITP). A relation between the ADR frequency and elevated infusion rates or high dosages was not detected. CONCLUSIONS: This unique 10-year observational study demonstrates that Octagam is well tolerated in routine clinical use with an overall ADR frequency of 0.35%.

Asunto(s)

Enfermedades Autoinmunes/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND: Since information on the efficacy of hyperthermia in combination with chemotherapy on pediatric tumors is limited, we performed a systematic analysis on the synergistic effects of a combined application of heat and chemotherapy on 20 tumor cell lines derived from patients with neuroblastomas, Ewing tumors, germ cell tumors (GCT), and osteosarcomas. METHODS: Cisplatin (cDDP), a cross-linking agent, and etoposide (VP-16), a topoisomerase II inhibitor, were examined either alone or in combination with heat (42 degrees C, 43 degrees C) by using the XTT-assay 1. RESULTS: Our data demonstrate that heat stress at 43 degrees C for 1 hr, but not at 42 degrees C, leads to a notable cytotoxic effect on the different tumor cells. The comparison of mean survival fractions reveals values between 62% for neuroblastoma cells and 76% for Ewing tumor cells. Analyzing the sensitivity to chemotherapy alone, our results show that cDDP (5 microg/ml) reduces cell growth to 47% in Ewing tumor cells, to 61% in neuroblastoma cells, to 75% in GCT cells, and to 76% in osteosarcoma cells. Treatment with VP-16 (10 microg/ml) decreases cell survival to mean values between 58% (neuroblastomas) and 77% (osteosarcomas). Simultaneous application of heat and chemotherapy enhances synergistically cDDP cytotoxicity in all tumor types tested, whereas the efficacy of VP-16 is only slightly influenced by additional application of hyperthermia. The cytotoxicity of cDDP (5 microg/ml) can be increased by a factor of between 1.5 and 2.5 at 42 degrees C and from 2.6 to 14.0 at 43 degrees C. Furthermore, the results show that the sensitivity to heat (43 degrees C) as well as the sensitivity to chemotherapy and combined thermochemotherapy varies considerably between cell lines of the same tumor group. CONCLUSIONS: Simultaneous application of hyperthermia synergistically enhances the cytotoxicity of the alkylating agent cDDP, but not of the topoisomerase II inhibitor VP-16, in a defined spectrum of cell lines from different pediatric tumor entities.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias Óseas/patología , Línea Celular Tumoral/patología , Hipertermia Inducida , Neoplasias de Células Germinales y Embrionarias/patología , Neuroblastoma/patología , División Celular , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular , Niño , Cisplatino/farmacología , Terapia Combinada , Reactivos de Enlaces Cruzados/farmacología , Etopósido/farmacología , Humanos , Inhibidores de Topoisomerasa II

RESUMEN

BACKGROUND: The bioflavonoid quercetin, a polyphenolic compound widely distributed in the plant kingdom, has been demonstrated to exert cytostatic activity against a variety of tumor cells in vitro and in vivo. It may be useful in cancer therapy as a thermosensitizer by increasing the cell killing effect of hyperthermia and chemotherapy because of its ability to suppress heat-shock protein expression. MATERIALS AND METHODS: We investigated the effect of quercetin combined with two cytotoxic agents, cDDP (cis-diamminedichloroplatinum II) and VP-16 (etoposide), under various heat-shock conditions in two Ewing's tumor cell lines SK-ES-1 and RD-ES, using XTT-assay and Western blot analysis. RESULTS: Induction of thermotolerance by a sublethal heat-shock (42 degrees C, 1 hour) led to a transient resistance against subsequent heat treatment alone or combined thermochemotherapy with the crosslinking agent cDDP or the topoisomerase II inhibitor VP-16. Quercetin (> or = 50 microM) applied for 24 hours inhibited cell proliferation, increased the cytotoxic activity of cDDP or VP-16 alone or combined with simultaneous hyperthermia and suppressed the development of thermotolerance. Hyperthermia (43 degrees C, 45 degrees C for 1 hour) induced high expression of the inducible form of HSP70, whereas HSP27, which is constitutively expressed at normothermic conditions, is only slightly induced by 43 degrees C and nearly completely suppressed at 45 degrees C. Induction of thermotolerance is accompanied by an elevated expression of both HSP70 and HSP27. Quercetin (> or = 50 microM), alone as well as in combination with thermochemotherapy, inhibited the expression of both HSP70 and HSP27. CONCLUSION: These data suggest that the bioflavonoid quercetin potentially may be useful in clinical trials for optimizing the efficacy of hyperthermia in combination with chemotherapy.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Choque Térmico , Hipertermia Inducida , Quercetina/farmacología , Sarcoma de Ewing/terapia , Cisplatino/administración & dosificación , Terapia Combinada , Sinergismo Farmacológico , Etopósido/administración & dosificación , Proteínas de Choque Térmico HSP27 , Proteínas HSP70 de Choque Térmico/biosíntesis , Humanos , Chaperonas Moleculares , Proteínas de Neoplasias/biosíntesis , Quercetina/administración & dosificación , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/metabolismo , Células Tumorales Cultivadas

RESUMEN

Recessive mutations of the Drosophila gene lethal(2)-tumorous imaginal discs (l(2)tid) cause neoplastic growth of the anlagen of the adult organs, the imaginal discs. Here we report that the three proteins encoded by this evolutionarily conserved gene, Tid50, Tid47, and Tid40, identified as members of the DnaJ cochaperone family, are destined for different cellular compartments, build complexes with many proteins in a developmental stage-specific manner, and are likely to be involved in different cellular processes. We show that the cytosolic Tid47 molecule is a novel component of the Hedgehog (Hh)-Patched (Ptc) signaling regulating cell/tissue polarity and spatial patterning during development and is associated with human tumors such as basal cell carcinoma (BCC) and medulloblastoma. We provide functional evidence for its direct in vivo interaction with the Hh-bound Ptc receptor during signal transmission. Because loss of l(2)tid causes neoplastic transformation of Hh-responsive cells, we suggest that Tid47 may at least act as a guardian of the Hh signaling gradient by regulating Ptc homeostasis in the tissue. Finally, we show that the expression of htid-1, the human counterpart of l(2)tid, is altered in human BCCs. We demonstrate that in BCCs loss of htid expression correlates with loss of differentiation capacity of the neoplastic cells similar to that found in the Drosophila tumor model.

Asunto(s)

Carcinoma Basocelular/genética , Proteínas de Drosophila , Drosophila/genética , Proteínas de Choque Térmico/genética , Proteínas de la Membrana/genética , Neoplasias Cutáneas/genética , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Basocelular/patología , Diferenciación Celular , Polaridad Celular , Transformación Celular Neoplásica/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Mapeo Cromosómico , Drosophila/crecimiento & desarrollo , Evolución Molecular , Femenino , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas del Choque Térmico HSP40 , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Humanos , Técnicas In Vitro , Larva/genética , Ligandos , Masculino , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteínas Mitocondriales , Receptores Patched , Fenotipo , Estructura Terciaria de Proteína , Receptores de Superficie Celular , Neoplasias Cutáneas/patología