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1.
Oncologist ; 25(2): e328-e334, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043777

RESUMO

On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD occurring after allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered at 5 mg twice daily, with dose increases to 10 mg twice daily permitted after 3 days in the absence of toxicity. The Day-28 overall response rate was 57.1% (95% confidence interval [CI]: 42.2-71.2). The median duration of response was 0.5 months (95% CI: 0.3-2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable). Common adverse reactions included anemia, thrombocytopenia, neutropenia, infections, edema, bleeding, and elevated transaminases. Ruxolitinib is the first drug approved for treatment of SR-aGVHD. IMPLICATIONS FOR PRACTICE: Ruxolitinib is the first Food and Drug Administration-approved treatment for steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Its approval provides a treatment option for the 60% of those patients who do not respond to steroid therapy.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Nitrilas , Pirazóis/efeitos adversos , Pirimidinas , Esteroides/uso terapêutico
2.
Breast Cancer Res Treat ; 124(2): 349-60, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20155316

RESUMO

Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of adriamycin; furthermore, the combination of sildenafil with adriamycin was no more toxic to the animals than adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Animais , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Camptotecina/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Doxorrubicina/toxicidade , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/farmacologia , Inibidores da Fosfodiesterase 5/toxicidade , Piperazinas/toxicidade , Purinas/farmacologia , Purinas/toxicidade , Citrato de Sildenafila , Sulfonas/toxicidade , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Clin Cancer Res ; 26(3): 532-536, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31548341

RESUMO

Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%-81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2-12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN.


Assuntos
Células Dendríticas/efeitos dos fármacos , Aprovação de Drogas , Neoplasias Hematológicas/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Plasmocitoma/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Plasmocitoma/patologia , Resultado do Tratamento , Estados Unidos , Adulto Jovem
4.
Clin Cancer Res ; 25(11): 3205-3209, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692099

RESUMO

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 (95% CI, 5.6-12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.


Assuntos
Antineoplásicos/uso terapêutico , Aprovação de Drogas , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Piridinas/uso terapêutico , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Piridinas/farmacologia , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
5.
Clin Cancer Res ; 25(20): 6021-6025, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31064779

RESUMO

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.See related commentary by Fathi, p. 6015.


Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Citarabina/administração & dosagem , Aprovação de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Comorbidade , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Rotulagem de Medicamentos , Feminino , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Receptor Smoothened/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
6.
Clin Cancer Res ; 25(9): 2685-2690, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541745

RESUMO

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aprovação de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos/administração & dosagem , Adulto , Idoso , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Lipossomos/química , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
7.
Clin Cancer Res ; 24(14): 3242-3246, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29476018

RESUMO

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Aprovação de Drogas , Gemtuzumab/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Adulto , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gemtuzumab/farmacologia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Resultado do Tratamento
8.
J Immunotoxicol ; 14(1): 215-227, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29141474

RESUMO

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B6C3F1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B6C3F1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5-7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice.


Assuntos
Cromatos/toxicidade , Cromo/toxicidade , Água Potável , Poluentes Ambientais/toxicidade , Células Matadoras Naturais/imunologia , Animais , Exposição Ambiental/efeitos adversos , Água Subterrânea , Humanos , Imunidade Humoral , Imunidade Inata , Imunoglobulina M/sangue , Imunomodulação , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
9.
Clin Cancer Res ; 21(5): 950-4, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25601959

RESUMO

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Aprovação de Drogas , United States Food and Drug Administration , Adulto , Idoso , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos
10.
Toxicol Sci ; 122(1): 7-15, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21498876

RESUMO

Drug-induced vascular injury (DIVI) is observed in rat mesenteric arterioles in response to treatment with phosphodiesterase-4 inhibitors (PDE4i). However, the mechanisms responsible for causing the characteristic vascular lesions are unclear. Nitrotyrosine (NT) adducts, markers of local nitric oxide (NO) production, have been observed in close proximity to the arterial lesions and in the inflammatory cells associated with DIVI. To determine if NO has a direct role in DIVI, rats were treated with the PDE4i CI-1044 at 10, 20, or 40 mg/kg alone or in combination with the nitric oxide synthase inhibitor L-NAME (60 mg/kg) or the nitric oxide donor SIN-1 (30 mg/kg). Mesenteries were collected and processed for microscopic evaluation. NT formation was evaluated in situ via immunohistochemical staining. Serum nitrite (SN), a marker of in vivo NO production, was measured. Compared with vehicle controls, treatment with CI-1044 alone resulted in dose-related increases in the frequency and severity of vascular injury, SN levels, and NT residues. SIN-1 coadministration caused vascular injury to occur at lower doses of CI-1044, compared with CI-1044 alone, with the overall incidence and severity of injury being greater across all CI-1044-dose groups. Following administration of 20 or 40 mg/kg CI-1044, there were also increases in NT immunoreactivity when SIN-1 was coadministered and significant increases in SN. Conversely, coadministration of L-NAME resulted in marked reduction of injury, NT, and SN when compared with CI-1044 alone. The present study suggests that NO production is closely linked to PDE4i-induced vascular injury.


Assuntos
Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 4/metabolismo , Lesões do Sistema Vascular/induzido quimicamente , Animais , Azepinas/efeitos adversos , Biomarcadores/análise , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Imuno-Histoquímica , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/patologia , Molsidomina/análogos & derivados , Molsidomina/metabolismo , NG-Nitroarginina Metil Éster/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Óxido Nítrico/análise , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Ratos , Ratos Sprague-Dawley , Tirosina/análogos & derivados , Tirosina/análise
11.
J Immunotoxicol ; 7(4): 333-43, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20958156

RESUMO

Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B6C3F1 mice, at concentrations of 125, 500, and 1000 mg/L. Multiple endpoints were evaluated to assess innate, humoral, and cell-mediated immune components, as well as host resistance. Standard toxicological parameters were unaffected, with the exception of a dose-responsive increase in liver weight and a decrease in thymus weight at the two highest exposure levels. Splenocyte differentials were affected, although the effects were not dose-responsive. Exposure to DBA did not significantly affect humoral immunity (immunoglobulin M [IgM] plaque assay and serum IgM anti-sheep erythrocyte titers) or cell-mediated immunity (mixed-leukocyte response). No effects were observed on innate immune function in either interferon-γ-induced in vitro macrophage cytotoxic activity or basal natural killer (NK)-cell activity. Augmented NK-cell activity (following exposure to polyinosinic-polycytidylic acid) was decreased at the low dose, however the effect was not dose-responsive. Finally, DBA exposure had no effect on resistance to infection with either Streptococcus pneumoniae or Plasmodium yoelii, or challenge with B16F10 melanoma cells. With the exception of changes in thymus weight, these results indicate that DBA exposure resulted in no immunotoxic effects at concentrations much larger than those considered acceptable in human drinking water.


Assuntos
Acetatos/administração & dosagem , Neoplasias Pulmonares/imunologia , Malária/imunologia , Melanoma Experimental/imunologia , Plasmodium yoelii/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Timo/efeitos dos fármacos , Animais , Citotoxicidade Imunológica/efeitos dos fármacos , Desinfecção , Feminino , Imunidade Ativa/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Malária/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos , Plasmodium yoelii/patogenicidade , Infecções Pneumocócicas/tratamento farmacológico , Streptococcus pneumoniae/patogenicidade , Timo/química , Água/administração & dosagem
12.
J Immunotoxicol ; 4(2): 153-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18958724

RESUMO

In rodents, the Plaque Assay, T-dependent antibody response to sheep erythrocytes (SRBC), has been reported to be a sensitive and predictive functional immune assay for detecting immunomodulatory compounds. However, various laboratories have chosen to use ELISA-based assays for evaluating the primary immune response in rodents. The ELISA-based assays offer several advantages over the Plaque Assay, which make them attractive for use in immunotoxicological evaluations. Among the most popular antigens used in the ELISA-based assays are SRBC and more recently KLH. While the Plaque Assay and the ELISA-based assays are both capable of evaluating the humoral immune response, they are measuring different endpoints. The Plaque Assay focuses primarily on splenic effects. ELISA-based assays, which use serum from immunized animals, are holistic in nature in that these assays measure effects of antibody production on the spleen, lymph nodes, and bone marrow. Depending on the drug or compound evaluated, different effects and degrees of sensitivity can be seen with the Plaque Assay and ELISA-based assays. One recent finding is that the sensitizing dose of KLH used in the KLH ELISA differentially affects the responses observed in rodents. Even within the same species, different strains of mice and rats produce different magnitudes of responses to the same sensitizing dose. A key component of this discussion focuses on the sensitivity of the Plaque Assay as compared to KLH ELISA-based assays. These assays were evaluated by comparing the response obtained following administration of several known immunosuppressive agents, including cyclophosphamide, azathioprine, cyclosporine A and dexamethasone. The effects on the primary IgM immune response in the B(6)C(3)F(1) mice, the primary immunotoxicological rodents used by National Toxicology Program, and in the Sprague-Dawley rat, the primary rodent models used by industry are addressed.

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