RESUMO
Interleukin-11 was developed to reduce chemotherapy-induced thrombocytopenia; however, its clinical use was limited by severe adverse effects in humans. PEGylated interleukin-11 (BBT-059), developed by Bolder Biotechnology, Inc., exhibited a longer half-life in rodents and induced longer-lasting increases in hematopoietic cells than interleukin-11. A single dose of 1.2 mg kg of BBT-059, administered subcutaneously to CD2F1 mice (12-14 wk, male) was found to be safe in a 14 d toxicity study. The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to Co gamma total-body irradiation. A single dose of 0.3 mg kg, administered either 24 h pre-, 4 h post-, or 24 h postirradiation increased the survival of mice to 70-100% from lethal doses of radiation. Preadministration (-24 h) of the drug conferred a significantly (p < 0.05) higher survival compared to 24 h post-total-body irradiation. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pretreated with BBT-059. The drug also increased bone marrow cellularity and megakaryocytes and accelerated multilineage hematopoietic recovery. In addition, BBT-059 inhibited the induction of radiation-induced hematopoietic biomarkers, thrombopoietin, erythropoietin, and Flt-3 ligand. These results indicate that BBT-059 is a promising radiation countermeasure, demonstrating its potential to be used both pre- and postirradiation for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Sistema Hematopoético/efeitos dos fármacos , Interleucina-11/administração & dosagem , Polietilenoglicóis/química , Lesões Experimentais por Radiação/tratamento farmacológico , Irradiação Corporal Total/efeitos adversos , Síndrome Aguda da Radiação/etiologia , Animais , Relação Dose-Resposta à Radiação , Sistema Hematopoético/patologia , Sistema Hematopoético/efeitos da radiação , Interleucina-11/química , Masculino , Camundongos , Lesões Experimentais por Radiação/etiologiaRESUMO
The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2=6.9h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1-0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100µg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.
Assuntos
Interleucina-11/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Injeções Subcutâneas , Interleucina-11/química , Interleucina-11/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macaca fascicularis , Masculino , Polietilenoglicóis/química , Polietilenoglicóis/toxicidade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/toxicidadeRESUMO
The incidence of cancer is constantly increasing. Chemo/radiotherapy is one of major methods of treating cancer. Although adverse chemo/radiotherapy events, such as anemia and neutropenia, can be successfully cured, thrombocytopenia is still problematic. We constructed the Hyper-IL11 (H11) cytokine by linking soluble interleukin 11 receptor alpha (sIL-11Ralpha) with IL-11. In vivo H11 activity was examined in myelosuppressed mice. Myelosuppression was induced by either i) sublethal irradiation and carboplatin administration or ii) sublethal irradiation. A dose of 100 µg/kg of H11 or IL-11 was administered subcutaneously for 7 days. IL-11 and H11 accelerated leukocyte, hematocrit and platelet recovery. The effect on the attenuation of thrombocytopenia was significant. Moreover, both cytokines increased the cellularity and numbers of megakaryocyte, erythroid, and granulocyte/macrophage progenitors in the bone morrow and spleen compared with the control. Although H11 was administered at a molar concentration that was three times lower, its effects were comparable with or better than those of IL-11; thus, the activity of H11 was superior to that of IL-11. Because no toxicity was observed after the intravenous administration of H11, this hyper-cytokine may be potentially useful for treatment of thrombocytopenia and other IL-11-dependent disorders.
Assuntos
Hematopoese/efeitos dos fármacos , Interleucina-11/administração & dosagem , Trombocitopenia/tratamento farmacológico , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Ensaio de Unidades Formadoras de Colônias , Drogas Desenhadas/administração & dosagem , Modelos Animais de Doenças , Feminino , Hematopoese/imunologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Subunidade alfa de Receptor de Interleucina-11/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/administração & dosagem , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Trombocitopenia/patologiaRESUMO
We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients.
Assuntos
Cardiotônicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Interleucina-11/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Administração Intravenosa , Idoso , Cardiotônicos/administração & dosagem , Angiografia Coronária , Drogas em Investigação/administração & dosagem , Humanos , Interleucina-11/administração & dosagem , Masculino , Contração Miocárdica/efeitos dos fármacos , Intervenção Coronária Percutânea , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Whole-cell-based vaccines modified with Hyper-IL-6 (H6) and Hyper-IL-11 (H11) have demonstrated high activity in murine melanoma and renal cancer models. MATERIALS AND METHODS: H6 and H11 cDNA was transduced into TRAMP cells (TRAMP-H6 and TRAMP-H11). An orthotopic TRAMP model was employed. The efficacy of TRAMP-H6 and TRAMP-H11 in combination with docetaxel was evaluated. Immune cells infiltrating tumors were assessed. RESULTS: Immunization with TRAMP-H6 and TRAMP-H11 vaccines extended OS of mice. Addition of docetaxel to TRAMP-H6 and TRAMP-H11 vaccines further extended OS of the animals. Vaccination with TRAMP-H6 alone and TRAMP-H11 combined with docetaxel augmented tumor infiltration by activated CD8(+) and CD4(+) T-cells and attracted higher number of activated, mature DCs infiltrating tumors. Addition of docetaxel to TRAMP-H6, TRAMP-H11, TRAMP-Adv700 vaccines enhanced the infiltration of the tumor by NK cells. CONCLUSION: Addition of docetaxel to modified TRAMP vaccines improved clinical benefit of treated mice and enhanced anti-tumor immune response.
Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia , Interleucina-11/genética , Interleucina-6/genética , Neoplasias da Próstata/tratamento farmacológico , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Modelos Animais de Doenças , Docetaxel , Humanos , Interleucina-11/administração & dosagem , Interleucina-6/administração & dosagem , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Células-Tronco Neoplásicas/imunologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Proteínas Recombinantes de Fusão/imunologia , Taxoides/administração & dosagemRESUMO
This study investigated the radioprotective effect of Sipunculus nudus L. polysaccharide (SNP) in combination with WR-2721, rhIL-11 and rhG-CSF on irradiated mice. A total of 70 Imprinting Control Region (ICR) mice were divided into seven groups: the control group, the model group and five administration groups. All groups, except the control group, were exposed to a 5 Gy (60)Co γ-ray beam. Blood parameters [including white blood cell (WBC), red blood cell (RBC) and platelet counts and hemoglobin level] were assessed three days before irradiation, and the on the 3rd, 7th and 14th days after irradiation. Spleen, thymus and testicular indices, DNA contents of bone marrow cells, bone marrow nucleated cells, sperm counts, superoxide dismutase (SOD), malondialdehyde (MDA), testosterone and estradiol levels in the serum were assessed on the 14th day after irradiation. The combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF exerted synergistic recovery effects on peripheral blood WBC, RBC and platelet counts and hemoglobin levels in irradiated mice, and synergistic promotion effects on spleen, thymus, testicle, bone marrow nucleated cells and sperm counts in irradiated mice. The synergistic administration increased the serum SOD activities and serum testosterone content of irradiated mice, but synergy decreased the content of serum MDA and estradiol in irradiated mice. These results suggest that the combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF should increase the efficacy of these drugs for acute radiation sickness, protect immunity, hematopoiesis and the reproductive organs of irradiated-damaged mice, and improve oxidation resistance in the body.
Assuntos
Amifostina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Interleucina-11/administração & dosagem , Nematoides/química , Polissacarídeos/administração & dosagem , Lesões por Radiação/prevenção & controle , Animais , Quimioterapia Combinada/métodos , Fator Estimulador de Colônias de Granulócitos/genética , Interleucina-11/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Lesões por Radiação/diagnóstico , Lesões por Radiação/fisiopatologia , Protetores contra Radiação/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the effects of the pretreatment and treatment with recombinant human interleukin-11 (rhIL-11) on acute liver failure induced by D-galactosamine (D-GalN). METHODS: The Sprague Dawley (SD) male rats were randomly divided into five groups: control, model, pretreatment, treatment and repeated treatment groups. The acute liver failure model was established by intraperitoneal injections with D-GalN (1400 mg/kg). The pretreatment, treatment and repeated treatment groups were injected subcutaneously with rhIL-11 (500 µg/kg). The rats were killed 24, 48, or 72 h after the D-GalN injection. The symptoms and survival rate of the rats were analysed. Liver injury was assessed by serum ALT and AST levels and by histological analysis. The percentage of Proliferating Cell Nuclear Antigen (PCNA+) cells in the liver tissue was evaluated by immunohistochemistry. RESULTS: Compared with the model group, the survival rate of the pretreatment group improved markedly, and these rats were protected from severe hepatic injury, as shown by the decreased serum ALT and AST levels and improved histological results. In the pretreatment group, the percentage of PCNA+ cells was significantly increased in the late stage. In contrast, the treatment and repeated treatment groups did not show improved survival rates or the prevention of severe hepatic injury, as shown by the absence of any decrease in the serum ALT and AST levels and the lack of any improvement in the histological results.The treatment and repeated treatment groups also have a significant increase in the percentage of PCNA+ cells in the late stage. CONCLUSIONS: The pretreatment with rhIL-11 can reduce acute liver failure and protect the liver. In contrast, the treatment with rhIL-11 cannot reduce acute liver failure or protect the liver.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Galactosamina , Interleucina-11/administração & dosagem , Falência Hepática Aguda/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citoproteção , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Fígado/enzimologia , Fígado/patologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Fatores de TempoRESUMO
Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/efeitos dos fármacos , Interleucina-11/farmacologia , Polietilenoglicóis/química , Síndrome Aguda da Radiação/fisiopatologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/química , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/química , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematopoese/efeitos da radiação , Humanos , Interleucina-11/administração & dosagem , Interleucina-11/química , Interleucina-11/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Análise de Sobrevida , Adulto JovemRESUMO
Countermeasures against radiation are critically needed. Ideally, these measures would be easy to store, easy to administer and have minimal toxicity. We used oral delivery of interleukin 11 (IL11) in mice exposed to lethal doses of total-body irradiation (TBI). Animals were given IL11 by gavage at various daily doses beginning 24 h after TBI, which continued for 5 days. At a TBI of 9.0 Gy, mice treated with IL11 had a 70% survival at 30 days compared with control group survival of 25% (P = 0.035). At 10.0 Gy, treated animals had 50% survival at 30 days compared with no survivors in the control group. Treated animals had significant improvement in intestinal mucosal surface area and crypt survival. In addition bacterial translocation of coliform bacteria was significantly less in the treated animals. Systemic absorption of IL11 was low in treated animals and effects on the hematopoietic cells were not seen. Serum citrulline levels rebounded significantly faster after irradiation in the IL11 treated animals, indicating quicker recovery of small intestine health. These data suggest that IL11 given orally protects the intestinal mucosa from radiation damage and that this compound is beneficial as a mitigating agent even when started 24 h after radiation exposure.
Assuntos
Interleucina-11/administração & dosagem , Interleucina-11/farmacologia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/farmacologia , Irradiação Corporal Total/efeitos adversos , Administração Oral , Animais , Humanos , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Masculino , Camundongos , Análise de SobrevidaRESUMO
OBJECTIVE: To evaluate the effect of recombinant human interleukin 11 (rhIL-11) on hematological recovery after autologous hematopoietic stem cell transplantation (AHSCT) in patients with lymphoma. METHODS: A retrospective study was carried out on 73 patients with lymphoma after AHSCT. The patients were divided into two groups. The study group (n = 35) received rhIL-11 1.5 mg daily from the fifth day after AHSCT to the day when platelets recovering to 80.0×109/L. The control group (n = 38) did not receive rhIL-11 after AHSCT. RESULTS: All the 73 patients finished AHSCT from Mar 2003 to Dec 2008 in our department. Thirty-five patients received rhIL-11 and 38 patients did not. In the rhIL-11 group and control group, the nadir of platelet was (18.9 ± 5.0)×109/L and (21.5 ± 6.0)×109/L, respectively, with a significant difference (P = 0.04). The median time of platelet recovering to 50.0×109/L was (14.3 ± 5.5) d and (13.2 ± 4.5) d (P = 0.37) in the two groups. There was no significant difference (P = 0.82) in the median numbers of platelet transfusion in the two groups. The curves of the mean of daily absolute platelet counts of the two groups were similar (P = 0.22). Adverse events related to rhIL-11 were not found in the rhIL-11 group. CONCLUSION: The results of this study do not show obviously accelerating effect of rhIL-11 on the platelet recovery in lymphoma patients after AHSCT and obvious increase of adverse events after rhIL-11 administration.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Interleucina-11/administração & dosagem , Linfoma/terapia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Contagem de Plaquetas , Transfusão de Plaquetas , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Transplante AutólogoRESUMO
Activation of cardiac STAT3 by IL-6 cytokine family contributes to cardioprotection. Previously, we demonstrated that IL-11, an IL-6 cytokine family, has the therapeutic potential to prevent adverse cardiac remodeling after myocardial infarction; however, it remains to be elucidated whether IL-11 exhibits postconditioning effects. To address the possibility that IL-11 treatment improves clinical outcome of recanalization therapy against acute myocardial infarction, we examined its postconditioning effects on ischemia/reperfusion (I/R) injury. C57BL/6 mice were exposed to ischemia (30 min) and reperfusion (24 h), and IL-11 was intravenously administered at the start of reperfusion. I/R injury mediated the activation of STAT3, which was enhanced by IL-11 administration. IL-11 treatment reduced I/R injury, analyzed by triphenyl tetrazolium chloride staining [PBS, 46.7 ± 14.4%; IL-11 (20 µg/kg), 28.6 ± 7.5% in the ratio of infarct to risk area]. Moreover, echocardiographic and hemodynamic analyses clarified that IL-11 treatment preserved cardiac function after I/R. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining revealed that IL-11 reduced the frequency of apoptotic cardiomyocytes after I/R. Interestingly, IL-11 reduced superoxide production assessed by in situ dihydroethidium fluorescence analysis, accompanied by the increased expression of metallothionein 1 and 2, reactive oxygen species (ROS) scavengers. Importantly, with the use of cardiac-specific STAT3 conditional knockout (STAT3 CKO) mice, it was revealed that cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of I/R injury. Finally, IL-11 failed to suppress the ROS production after I/R in STAT3 CKO mice. IL-11 administration exhibits the postconditioning effects through cardiac STAT3 activation, suggesting that IL-11 has the clinical therapeutic potential to prevent I/R injury in heart.
Assuntos
Cardiotônicos/administração & dosagem , Interleucina-11/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Humanos , Injeções Intravenosas , Metalotioneína/genética , Metalotioneína/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Interferência de RNA , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Fatores de Tempo , Transfecção , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacosRESUMO
Lack of effective treatment for menorrhagia is the greatest unmet healthcare need in women with von Willebrand disease (VWD). We conducted a single-centre phase II clinical trial to determine efficacy and safety of recombinant IL-11 (rhIL-11, Neumega®) given subcutaneously for up to seven days during six consecutive menstrual cycles each in seven women with mild VWD and menorrhagia refractory to haemostatic or hormonal agents. rhIL-11 reduced menstrual bleeding severity as measured by pictorial blood assessment chart (PBAC) ≥ 50% (to <100) in 71% of subjects, cycle severity ≥ 50% in 71%, and bleeding duration ≥ 2 days in 85%, all p ≤ 0.01. After rhIL-11, plasma VWF:RCo increased 1.1-fold, but did not correlate with PBAC, r=0.116, bleeding duration, r=0.318, or cycle severity, r=-0.295, or hsCRP, r=-0.003, all p>0.05. Platelet VWF mRNA expression by quantitative PCR increased mean four-fold (1.0-13.5). rhIL-11 was well tolerated with grade 1 or less fluid retention, flushing, conjunctival erythema, and local bruising. In summary, rhIL-11 reduces menorrhagia safely and warrants further study.
Assuntos
Plaquetas/efeitos dos fármacos , Imunoterapia , Interleucina-11/administração & dosagem , Menorragia/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Doenças de von Willebrand/tratamento farmacológico , Adolescente , Adulto , Plaquetas/metabolismo , Plaquetas/patologia , Progressão da Doença , Resistência a Medicamentos , Eritema/etiologia , Feminino , Humanos , Injeções Subcutâneas , Interleucina-11/efeitos adversos , Menorragia/sangue , Menorragia/etiologia , Menorragia/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Saúde da Mulher/tendências , Doenças de von Willebrand/sangue , Doenças de von Willebrand/complicações , Doenças de von Willebrand/imunologia , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
OBJECTIVE: To investigate and evaluate the clinical therapeutic effect of low-dose interleukin-11 treatment of thrombocytopenia in patients with malignant hematologic diseases after chemotherapy. METHODS: 70 patients with hematologic malignancies including acute leukemia, lymphoma and multiple myeloma were randomly divided into treatment group (35 cases) and control group (35 cases) and were treated with chemotherapy. Cases in the treatment group received subcutaneous injection of interleukin-11 (50 µg × kg(-1) × d(-1)) until platelet counting recovered ≥ 50 × 10(9)/L, while cases in the control group were not administrated with interleukin-11. RESULTS: The mean time of platelet recovery in the treatment group was 9.6 days, significantly shorter than that (14.0 days) in the control group (P < 0.05). The minimum platelet counting in the treatment group was significantly higher than that in the control group (16.2 × 10(9)/L vs. 11.6 × 10(9)/L, P < 0.05). The mean times of platelet infusion after chemotherapy in the treatment group and control group were 2.88 and 2.98, respectively (P > 0.05). CONCLUSION: Administration of interleukin-11 in thrombocytopenic patients with hematologic malignancies after chemotherapy may not only remarkably enhance platelet counts and shorten the recovery time of thrombocytopenia, but also has only mild side effects.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Interleucina-11/uso terapêutico , Leucemia/tratamento farmacológico , Trombocitopenia/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Interleucina-11/administração & dosagem , Linfoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Contagem de Plaquetas , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.
Assuntos
Interleucina-11/administração & dosagem , Doenças de von Willebrand/tratamento farmacológico , Adulto , Desamino Arginina Vasopressina/efeitos adversos , Desamino Arginina Vasopressina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Fator VIII/metabolismo , Feminino , Hemostáticos/efeitos adversos , Hemostáticos/uso terapêutico , Humanos , Injeções Subcutâneas , Interleucina-11/efeitos adversos , Interleucina-11/uso terapêutico , Masculino , Contagem de Plaquetas , Reação em Cadeia da Polimerase/métodos , Estudos Prospectivos , RNA Mensageiro/genética , Proteínas Recombinantes/uso terapêutico , Adulto Jovem , Doenças de von Willebrand/sangue , Fator de von Willebrand/biossíntese , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
This study was aimed to evaluate the effects of recombinant human interleukin 11 (rhIL-11) and recombinant human granulocyte colony stimulating factor (rhG-CSF) in mobilization for autologous peripheral blood stem cell transplantation (APBSCT). 16 patients with non-Hodgkin's lymphoma or acute myeloblastic leukemia were given myelosuppressive chemotherapy, then were mobilized by using rhG-CSF 5 microg/(kg.d) for median 5.5 days and rhIL-11 50 microg/(kg.d) for median 4 days (experimental group) or rhG-CSF 5 microg/(kg.d) alone for median 5.5 days (control group). After mobilizing, the peripheral blood leucocyte and platelet counts, total mononuclear cells, CD34+ cells and CFU-GM counts in PBSC collection, and amount of apheresed platelet transfusion were assayed. The results showed that the peripheral blood leucocyte and platelet counts, total mononuclear cell, CD34+ cell and CFU-GM counts in PBSC collection were no significant difference between two groups (p>0.05). After APBSCT, the median time for neutrophil count>or=0.5x10(9)/L and the median time for platelet count>or=20x10(9)/L were 10.5 and 11.5 days in experimental group, while were 13 and 13 days in control group, respectively. The median amount of apheresed platelet transfusion was 3.5 unit in experimental group and 5 unit in control group. Data were significantly different between two groups (p<0.05). The adverse reactions of mobilization were mild fever, fatigue, symptoms like as common cold, poor appetite, dizziness, muscular soreness in experimental group, but only mild fever in control. These symptoms were well tolerated and overcome with drug withdrawal. It is concluded that the regimen of rhIL-11 in combination with rhG-CSF after myelosuppressive chemotherapy to mobilize PBSC is efficient and safe with rapid hematologic reconstitution and less platelet transfusions after APBSCT were used.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Interleucina-11/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Feminino , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Proteínas Recombinantes , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Immune thrombocytopenic purpura (ITP) is frequently associated with chronic hepatitis C (HpC-ITP). METHODS: Recombinant interleukin-11 (rIL-11), which has both thrombopoietic and anti-inflammatory properties, was evaluated in 12 patients with HpC-ITP in this pilot study. Group 1 (7 patients) was treated at high dose (50 microg/kg daily) while group 2 (5 patients) at low dose (15-35 microg/kg three/week). RESULTS: In group 1, mean platelet counts rose from initial 54 x 10(9)/l to 103 x 10(9)/l (p = 0.02) and in group 2, from an initial 51 x 10(9)/l to 74 x 10(9)/l (p = 0.04). Antiplatelet antibody (aPlt-Ab) decreased in group 1. LFT improved in both groups. The mean HCV-RNA decreased in group 1 (p = 0.04), not in group 2. Side effects were common and troublesome, but were minimized with individualized dosing. One patient achieved good remission of both ITP and HpC lasting >2 years with low-dose maintenance. CONCLUSION: When used based on individual tolerance, rIL-11 appears useful in HpC-ITP.
Assuntos
Hepatite C/complicações , Interleucina-11/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Anticorpos/sangue , Plaquetas/imunologia , Feminino , Humanos , Interleucina-11/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/etiologia , RNA Viral/sangue , Resultado do TratamentoRESUMO
To investigate the efficacy of using recombinant human interleukin 11 (rhIL-11) to reduce the need for platelet transfusions, we performed a randomized, double-blind phase II/III study with 110 acute myelogenous leukemia (AML) patients in the first complete remission. Following chemotherapy patients were subcutaneously administered either placebo (n=37) or rhIL-11 at a dose of 25 microg/kg (n=37) or 50 microg/kg (n=36). rhIL-11 administration was well tolerated. There was no difference between the rhIL-11 and placebo groups in the frequency and volume of platelet transfusions. In a perprotocol analysis set (101 patients), the platelet transfusion frequency in the 50-microg/kg group (3.0 +/- 1.76 times) was significantly lower than in the placebo group (3.9 +/-2.35 times; multiplicity-adjusted P= .049). We analyzed infection-related events retrospectively. The frequency of fever was significantly decreased in the 50-microg/kg, 25-microg/kg, and placebo groups (66.7%, 70.3%, and 89.2%, respectively; P= .018, Cochran-Armitage test). Stomatitis was less frequent in the 50-microg/kg and 25-microg/kg groups (2.8% and 0%, respectively) than in the placebo group (21.6%, P= .0012). These results show that rhIL-11 does not reduce the platelet transfusion requirement in AML patients, but the retrospective analysis confirms the previous finding that rhIL-11 reduces infection in patients undergoing chemotherapy.
Assuntos
Interleucina-11/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Infecções/tratamento farmacológico , Infecções/etiologia , Interleucina-11/farmacologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Placebos , Transfusão de Plaquetas , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Estomatite/tratamento farmacológico , Estomatite/etiologiaRESUMO
Heme oxygenase (HO)-1, the rate-limiting enzyme in heme catabolism, can be induced in response to various oxidative stimuli, and its induction is thought to be critical in the cellular defense against oxidative tissue injuries. Carbon tetrachloride (CCl(4)) treatment of rats causes lipid peroxidation of cell membranes and produces massive hepatic injury. We previously demonstrated that HO-1 induction following CCl(4) treatment is an essential part of the cellular defense against the CCl(4)-inducible toxic changes. As recombinant human interleukin-11 (rhIL-11) has been shown to induce HO-1 in cultured hepatoma cells, we examined the effect of rhIL-11 in vivo in rats on the CCl(4)-induced tissue injury. rhIL-11 treatment of animals by itself markedly induced HO-1 mRNA and its functional protein principally in the liver. rhIL-11 treatment (150 microg/kg) of the CCl(4)-administered (1 ml/kg) animals led to a further increase in HO-1 mRNA, while it markedly suppressed CCl(4)-induced serum alanine transaminase, hepatic malondialdehyde formation, tumor necrosis factor-alpha mRNA, nitric oxide synthase mRNA, nuclear factor-kappaB DNA-binding activity, as well as inflammatory changes of hepatocytes. In contrast, inhibition of HO activity by tin-mesoporphyrin, a competitive specific inhibitor of HO, entirely abolished the cytoprotective effect of rhIL-11. These findings thus demonstrate that rhIL-11 confers significant protection against CCl(4)-induced hepatic injury by virtue of its liver-specific HO-1 induction.
Assuntos
Heme Oxigenase-1/genética , Interleucina-11/farmacologia , Hepatopatias/prevenção & controle , Fígado/enzimologia , Animais , Northern Blotting , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intravenosas , Interleucina-11/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/enzimologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset of patients with mild to moderate Crohn's disease (CD). The present study compared the efficacy of rhIL-11 versus prednisolone in remission induction in CD. METHODS: Patients with active CD were randomly assigned to receive either subcutaneous rhIL-11 (1 mg once weekly) and prednisolone placebo tablets, or active prednisolone (60 mg/day) and rhIL-11 placebo, for 12 weeks. Prednisolone/placebo was tapered after week 1, and patients were assessed every second week. RESULTS: Fifty-one patients received medication: 13/27 (rhIL-11) and 17/24 (prednisolone) completed 12 weeks of treatment. Remission rates (intent to treat) for rhIL-11 versus prednisolone were 4% versus 46% at week 4 (p < 0.001) and 19% versus 50% at week 6 (p < 0.05). Response to treatment (deltaCDAI > 100) was seen in 19% (rhIL-11) versus 63% (prednisolone) after 4 weeks (p < 0.002) and 37% versus 63% after 6 weeks (p = 0.1). After 12 weeks of treatment, it was observed that 22% (rhIL-11) versus 21% (prednisolone) had remained in remission. Frequent side effects of rhIL-11 included fever (n = 3), rash (4), arthralgia/arthritis (3), nausea/vomiting (3), and headache (6). CONCLUSION: rhIL-11 is well tolerated but significantly inferior when compared to prednisolone in short-term remission induction in patients with active CD. In this patient cohort, both treatments appeared to be poor in maintaining remission over a period of 3 months.
Assuntos
Anti-Inflamatórios/administração & dosagem , Doença de Crohn/tratamento farmacológico , Glucocorticoides/administração & dosagem , Interleucina-11/administração & dosagem , Prednisolona/administração & dosagem , Administração Oral , Anti-Inflamatórios/efeitos adversos , Método Duplo-Cego , Feminino , Glucocorticoides/efeitos adversos , Humanos , Injeções Subcutâneas , Interleucina-11/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Indução de Remissão , Resultado do TratamentoRESUMO
Randomized trials of substituting high-dose cytarabine (HiDAC) for standard dose cytarabine (SDAC) during induction therapy for newly diagnosed AML have not demonstrated an improvement in the complete remission (CR) rate. Phase II trials of the scheduled administration of HiDAC after SDAC suggest an improved outcome. The hematological complications of intensification are considerable. GM-CSF after chemotherapy improved the survival of older patients in a randomized trial. Recombinant human interleukin 11, a thrombopoietic cytokine, reduced the incidence of chemotherapy-induced thrombocytopenia in patients with solid tumors. Therefore, 34 patients were treated, with newly diagnosed AML less than 56 years of age, with daunorubicin 45 mg/m2 on days 1-3, cytarabine 100mg/m2 days 1-7 and cytarabine 2g/m2 for 12 h on days 8-10 (7+3+3). rhIL-11 (50 microg/kg/day,) and GM-CSF (250 microg/kg/day) were administered subcutaneously from day 11 until recovery. The complete remission rate was 59% (90% C.I. 43-73%). The median time to recovery of neutrophils to >500 and platelets to > or =20,000 microl(-1) was 27 days (95% C.I. 27-30 days) and 25 days (95% C.I. 24-29 days), respectively. The trial does not confirm the high CR rate observed in phase II trials, despite optimal supportive care.