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1.
Toxicol Sci ; 183(1): 93-104, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34240189

RESUMO

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.


Assuntos
Linfoma , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Animais , Testes de Carcinogenicidade , Feminino , Hiperplasia , Linfoma/induzido quimicamente , Linfoma/genética , Masculino , Camundongos , Camundongos Transgênicos
2.
Toxicol Appl Pharmacol ; 409: 115285, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069749

RESUMO

The OX40 receptor plays a crucial co-stimulatory role in T effector cell survival, expansion, cytokine production, and cytotoxicity to tumor cells; therefore, OX40 agonists are being evaluated as anti-cancer immunotherapies, especially in combination with checkpoint inhibitors. To support clinical development of BMS-986178 (an OX40 agonist antibody), two repeat-dose toxicity studies were conducted in cynomolgus monkeys. In the first study, BMS-986178 was administered intravenously (IV) once weekly for one month at doses from 30 to 120 mg/kg. BMS-986178 was well tolerated; surprisingly, immune function was suppressed rather than increased based on pharmacodynamic (PD) and flow cytometry readouts (e.g. T-cell dependent antibody response [TDAR]). To determine whether immune suppression was due to a bi-phasic response, a follow-up study was conducted at lower doses (1 and 10 mg/kg). Although receptor engagement was confirmed, immune function was still suppressed at both doses. In addition, treatment-emergent anti-drug antibodies (ADAs) at 1 mg/kg resulted in hypersensitivity reactions and reduced BMS-986178 exposure after repeated dosing, which precluded a full PD assessment at this dose. In conclusion, BMS-986178 was clinically well-tolerated by monkeys at weekly IV doses from 10 to 120 mg/kg (AUC[0-168] ≤ 712,000 µg●h/mL). However, despite target engagement, PD assays and other immune endpoints demonstrated immune suppression, not stimulation. Due to the inverted immune response at higher doses and the onset of ADAs, additional repeat-dose toxicity studies of BMS-986178 in monkeys (that would typically be required to support Phase 3 clinical trials and registration) would not add value for human safety assessment.


Assuntos
Anticorpos Monoclonais/imunologia , Imunidade/imunologia , Receptores OX40/imunologia , Linfócitos T/imunologia , Animais , Feminino , Seguimentos , Humanos , Imunoterapia/métodos , Macaca fascicularis , Masculino
3.
PLoS One ; 14(11): e0224402, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697704

RESUMO

PURPOSE: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders. METHODS: We tested 1005 children aged 2-11 years with the Randot Preschool stereo test, plus a cover/uncover test to detect heterotropia. Monocular visual acuity was assessed in both eyes using Keeler Crowded LogMAR visual acuity test for children aged 4 and over. RESULTS: Testability was very high: 65% in two-year-olds, 92% in three-year-olds and ~100% in older children. Normative values: In 389 children aged 2-5 with apparently normal vision, 6% of children scored nil (stereoblind). In those who obtained a threshold, the mean log threshold was 2.06 log10 arcsec, corresponding to 114 arcsec, and the median threshold was 100 arcsec. Most older children score 40 arcsec, the best available score. We found a small sex difference, with girls scoring slightly but significantly better. Test/retest reliability: ~99% for obtaining any score vs nil. Agreement between stereo thresholds is poor in children aged 2-5; 95% limit of agreement = 0.7 log10 arcsec: five-fold change in stereo threshold may occur without any change in vision. In children over 5, the test essentially acts only as a binary classifier since almost all non-stereoblind children score 40 arcsec. Specificity (true negative rate): >95%. Sensitivity (true positive rate): poor, <50%, i.e. around half of children with a demonstrable binocular vision abnormality score well on the Randot Preschool. CONCLUSIONS: The Randot Preschool is extremely accessible for even very young children, and is very reliable at classifying children into those who have any stereo vision vs those who are stereoblind. However, its ability to quantify stereo vision is limited by poor repeatability in children aged 5 and under, and a very limited range of scores relevant to children aged over 5.


Assuntos
Estrabismo/diagnóstico , Transtornos da Visão/diagnóstico , Testes Visuais/métodos , Visão Binocular/fisiologia , Idoso , Criança , Pré-Escolar , Percepção de Profundidade/fisiologia , Feminino , Humanos , Masculino , Exame Físico , Estrabismo/fisiopatologia , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia
4.
Transl Vis Sci Technol ; 8(1): 25, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30834173

RESUMO

PURPOSE: To describe a new stereotest in the form of a game on an autostereoscopic tablet computer designed to be suitable for use in the eye clinic and present data on its reliability and the distribution of stereo thresholds in adults. METHODS: Test stimuli were four dynamic random-dot stereograms, one of which contained a disparate target. Feedback was given after each trial presentation. A Bayesian adaptive staircase adjusted target disparity. Threshold was estimated from the mean of the posterior distribution after 20 responses. Viewing distance was monitored via a forehead sticker viewed by the tablet's front camera, and screen parallax was adjusted dynamically so as to achieve the desired retinal disparity. RESULTS: The tablet must be viewed at a distance of greater than ∼35 cm to produce a good depth percept. Log thresholds were roughly normally distributed with a mean of 1.75 log10 arcsec = 56 arcsec and SD of 0.34 log10 arcsec = a factor of 2.2. The standard deviation agrees with previous studies, but ASTEROID thresholds are approximately 1.5 times higher than a similar stereotest on stereoscopic 3D TV or on Randot Preschool stereotests. Pearson correlation between successive tests in same observer was 0.80. Bland-Altman 95% limits of reliability were ±0.64 log10 arcsec = a factor of 4.3, corresponding to an SD of 0.32 log10 arcsec on individual threshold estimates. This is similar to other stereotests and close to the statistical limit for 20 responses. CONCLUSIONS: ASTEROID is reliable, easy, and portable and thus well-suited for clinical stereoacuity measurements. TRANSLATIONAL RELEVANCE: New 3D digital technology means that research-quality psychophysical measurement of stereoacuity is now feasible in the clinic.

5.
Regul Toxicol Pharmacol ; 100: 35-44, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30291877

RESUMO

Protein therapeutics represent a rapidly growing proportion of new medicines being developed by the pharmaceutical industry. As with any new drug, an Occupational Exposure Limit (OEL) should be developed to ensure worker safety. Part of the OEL determination addresses bioavailability (BA) after inhalation, which is poorly understood for protein therapeutics. To explore this, male Sprague-Dawley rats were exposed intravenously or by nose-only inhalation to one of five test proteins of varying molecular size (10-150 kDa), including a polyethylene glycol-conjugated protein. Blood, lung tissue and bronchoalveolar lavage (BAL) fluid were collected over various time-points depending on the expected test protein clearance (8 minutes-56 days), and analyzed to determine the pharmacokinetic profiles. Since the BAL half-life of the test proteins was observed to be > 4.5 h after an inhalation exposure, accumulation and direct lung effects should be considered in the hazard assessment for protein therapeutics with lung-specific targets. The key finding was the low systemic bioavailability after inhalation exposure for all test proteins (∼≤1%) which did not appear molecular weight-dependent. Given that this study examined the inhalation of typical protein therapeutics in a manner mimicking worker exposure, a default 1% BA assumption is reasonable to utilize when calculating OELs for protein therapeutics.


Assuntos
Polietilenoglicóis/farmacocinética , Proteínas/farmacocinética , Administração por Inalação , Animais , Disponibilidade Biológica , Líquido da Lavagem Broncoalveolar/química , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Masculino , Concentração Máxima Permitida , Ratos Sprague-Dawley , Receptores Fc/metabolismo
6.
AAPS J ; 20(2): 28, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29417397

RESUMO

The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to "exaggerated" effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Imunoterapia/efeitos adversos , Modelos Animais , Neoplasias/terapia , Animais , Anticorpos Monoclonais/efeitos adversos , Produtos Biológicos/efeitos adversos , Receptores Coestimuladores e Inibidores de Linfócitos T/agonistas , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Especificidade da Espécie
7.
J Immunotoxicol ; 11(1): 1-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23746314

RESUMO

Observational and clinical studies have associated increased cancer risks with primary or acquired immunodeficiencies, autoimmunity, and use of immunotherapies to treat chronic inflammation (e.g. autoimmunity) or support organ engraftment. Understanding of the relationship between immune status and cancer risk is generally grounded in two juxtaposing paradigms: that the immune system protects the host via surveillance of tumors and oncogenic viruses (e.g. immunosurveillance model) and that chronic inflammation can augment tumor growth and metastasis (inflammation model). Whereas these models support a role of immune status in many cancers, they are insufficient to explain the disproportionate increase in B-cell lymphoma risk observed across patient populations with either chronic immunosuppression or inflammation. Evaluation for the presence of Epstein-Barr virus (EBV) in lymphomas obtained from various populations demonstrates a variable role for the virus in lymphomagenesis across patient populations. An evaluation of the DNA alterations found in lymphomas and an understanding of B-cell ontogeny help to provide insight into the unique susceptibility of lymphocytes, primarily B-cells, to oncogenic transformation. EBV-independent B-cell oncogenic transformation is driven by chronic antigenic stimulation due to either inflammation (as seen in patients with autoimmune disease or a tissue allograft) or to unresolved infection (as seen in immunosuppressed patients), and the transformation arises as a result of DNA damage from genomic recombination and mutation during class switching and somatic hypermutation. This model explains the increased background rate of lymphoma in some patients with autoimmunity, and highlights the challenge of resolving the confounding that occurs between disease severity and use of targeted immunotherapies to treat chronic inflammation. The ability to distinguish between disease- and treatment-related risk of lymphoma and an appreciation of the etiology of B-cell transformation is central to an improved risk assessment by scientists, clinicians and regulators, including the approval, labeling, and chronic use of immunotherapies.


Assuntos
Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/imunologia , Imunoterapia/métodos , Linfoma de Células B/terapia , Animais , Linfócitos B/virologia , Transformação Celular Neoplásica , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunomodulação , Linfoma de Células B/etiologia , Linfoma de Células B/imunologia , Medição de Risco
8.
J Immunotoxicol ; 10(1): 106-17, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23173903

RESUMO

Functional innate immune assessments, including phagocytosis and respiratory burst, are at the forefront of immunotoxicology evaluation in pre-clinical animal species. Although in the clinic and in academic science, phagocytosis, and respiratory burst assessments have been reported for over two decades, the implementation of phagocytosis and respiratory burst analyses in toxicology safety programs is just recently gaining publicity. Discussed herein are general methods, both microtiter plate-based and flow cytometric-based, for assessing phagocytosis and respiratory burst in pre-clinical species including mouse, rat, dog, and monkey. This methods-centric discussion includes a review of technologies and descriptions of method applications, with examples of results from analyses testing reported inhibitors (rottlerin, wortmannin, and SB203580) of phagocytosis and respiratory burst. Justification of implementation, strategic experimental design planning, and feasibility aspects of evaluating test article effects on phagocytosis and respiratory burst function are described within the context of a case study. The case study involves investigation of the effects of a small molecule p38 kinase inhibitor, BMS-582949, on phagocytosis and respiratory burst functions in rat and monkey neutrophils and monocytes in vitro, as well as ex vivo in these innate immune cells from monkeys administered BMS-582949 during a 1-week repeat dose investigative study. The results of the in vitro and ex vivo assessments demonstrated that BMS-582949 inhibited phagocytosis and respiratory burst. These findings correlated with incidences of opportunistic infections observed in rat and monkey toxicity studies.


Assuntos
Testes Imunológicos , Fagocitose/efeitos dos fármacos , Pirróis/efeitos adversos , Explosão Respiratória/efeitos dos fármacos , Triazinas/efeitos adversos , Acetofenonas/farmacologia , Androstadienos/farmacologia , Animais , Benzopiranos/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Imidazóis/farmacologia , Imunidade Inata/efeitos dos fármacos , Camundongos , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Piridinas/farmacologia , Pirróis/administração & dosagem , Ratos , Triazinas/administração & dosagem , Wortmanina
9.
Toxicol Sci ; 127(1): 159-68, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22331490

RESUMO

The toxicokinetics and toxicity profile of belatacept (LEA29Y), which blocks the CD28 costimulation pathway to prevent T-cell activation, were evaluated in cynomolgus monkeys. In the current study, 30 monkeys (five monkeys per sex per group) received an intravenous dose of belatacept (10, 22, or 50 mg/kg) once weekly for 6 months. An additional five monkeys per sex received saline intravenously and served as controls. Systemic exposure to belatacept was dose proportional and similar for both sexes. Multiple dosing resulted in moderate belatacept accumulation (1.6- to 1.9-fold). Belatacept was clinically well tolerated in monkeys, with no drug-related laboratory parameter changes or target organ toxicity observed, including a lack of nephrotoxicity. Drug-related changes, which were reversible and related to the pharmacology, included dose-dependent minimal/mild reduction in the size and number of lymphoid germinal centers of the spleen and lymph nodes and minimal reductions in serum IgG levels. No antibodies specific for belatacept were detected during the treatment period. There were no changes in peripheral blood or splenic lymphocyte subpopulations or indications of autoimmune-like inflammation, infection, or malignancy, including preneoplastic changes. Functional recovery of the immune system was noted at all doses by a robust antibody response to keyhole limpet hemocyanin following immunization 2 months after the last belatacept dose was administered. Thus, belatacept was well tolerated in monkeys treated for 6 months at weekly doses up to 50 mg/kg, which represented a 20-fold increase above exposures achieved by the approved maintenance dose in kidney transplant recipients. These findings support the belatacept safety profile and demonstrate that belatacept does not result in adverse renal effects.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Imunoconjugados/toxicidade , Imunossupressores/toxicidade , Macaca fascicularis , Linfócitos T/efeitos dos fármacos , Abatacepte , Animais , Formação de Anticorpos/imunologia , Área Sob a Curva , Antígenos CD28/metabolismo , Feminino , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/patologia , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Imunoconjugados/farmacocinética , Imunoglobulinas/sangue , Imunossupressores/farmacocinética , Injeções Intravenosas , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/patologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Linfócitos T/patologia , Testes de Toxicidade Crônica
10.
J Immunotoxicol ; 9(1): 121-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22136193

RESUMO

Epstein-Barr virus (EBV)-associated lymphomas are a known risk for immunosuppressed individuals. Non-clinical methods to determine the potential of new immunomodulatory compounds to produce EBV-associated lymphomas (hazard identification) have not been developed. Since lymphocryptovirus (LCV) in non-human primates (NHP) has similar characteristics to EBV in humans, a Roundtable meeting was held in October 2010 to explore how the potential for EBV-related lymphomas in humans can be assessed by using surrogate biomarkers for lymphoma risk in NHP toxicity studies. Stakeholders from regulatory agencies, academia, and industry came together to determine the research gaps and potential benefits and considerations of such an approach given the current state-of-the-science. Key conclusions from the discussion included considerations raised about the potential usefulness of LCV-related biomarkers from NHP studies since there is significant controversy over the reliability of using EBV viral load or EBV-specific T-lymphocytes to predict for lymphoproliferative disorders in transplant patients. In addition, there are technical challenges that need to be further addressed in order to develop methods to measure LCV viral load and LCV-specific T-lymphocytes from cynomolgus monkeys.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Infecções por Herpesviridae/virologia , Fatores Imunológicos/toxicidade , Lymphocryptovirus/patogenicidade , Linfoma/etiologia , Primatas , Testes de Toxicidade , Infecções Tumorais por Vírus/virologia , Animais , Biomarcadores/análise , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/imunologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Linfoma/diagnóstico , Linfoma/imunologia , Linfoma/virologia , Modelos Animais , Medição de Risco , Fatores de Risco , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/imunologia , Carga Viral
11.
J Rheumatol ; 34(12): 2365-73, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18050376

RESUMO

OBJECTIVE: The immunogenicity of abatacept, a selective costimulation modulator, administered intravenously, was assessed across Phase II and III trials in patients with rheumatoid arthritis (RA). METHODS: Two direct-format enzyme-linked immunosorbent assays evaluated antibody responses [whole abatacept molecule (CTLA-4 and Ig portion) and CTLA-4 portion only (Assay A)] in the Phase II trials. During the Phase III trials and 2-year open-label periods, a similar, but more sensitive, Assay B was employed. Serum samples collected prestudy, during treatment, and 56 and/or 85 days following the last dose were evaluated. Seropositive samples with anti-CTLA-4 reactivity and sufficiently low drug levels were further characterized for neutralizing activity (cell-based bioassay). RESULTS: A total of 2237 patients with both pre- and post-baseline serum samples were eligible for assessment. Of these, 62 (2.8%) patients demonstrated an anti-abatacept or anti-CTLA-4 response, determined using either Assay A or B. Using the more sensitive Assay B, 60 of 1990 patients (3.0%) demonstrated an antibody response to the whole abatacept molecule (n = 41, 2.1%) or the CTLA-4 portion (n = 19, 1.0%). Of the 1764 RA patients evaluated in the Phase III studies, 203 discontinued therapy and had sera collected 56 and/or 85 days after discontinuation. Patients who discontinued had a higher incidence of immunogenicity versus patients who did not discontinue (7.4% vs 2.6%, respectively). Of 20 patients positive for anti-CTLA-4 reactivity, 13 were eligible for assessment with the neutralization bioassay. Of these, 8 patients exhibited neutralizing activity. Seroconversion occurred with no adverse safety outcomes or effect on pharmacokinetic parameters. No consistent pattern was observed between antibody response and loss of efficacy (American College of Rheumatology 20 and Health Assessment Questionnaire responses). CONCLUSION: Abatacept was associated with a low incidence of immunogenicity in patients with RA and lacked any adverse sequelae.


Assuntos
Artrite Reumatoide/imunologia , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Abatacepte , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Masculino
12.
Arthritis Rheum ; 56(8): 2557-65, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17665452

RESUMO

OBJECTIVE: Treatment of rheumatoid arthritis and other autoimmune disorders with anti-tumor necrosis factor (anti-TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti-TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection. METHODS: Chronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti-murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon-gamma (IFNgamma) production by T cells, and cellular infiltration were also assessed. RESULTS: Abatacept- and vehicle-treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNgamma production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti-TNF antibody-treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti-TNF antibody-treated group had increased pathology consistent with the exacerbation of M tuberculosis infection. CONCLUSION: Abatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti-TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.


Assuntos
Antirreumáticos/efeitos adversos , Imunoconjugados/efeitos adversos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Abatacepte , Animais , Anticorpos/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Interferon gama/metabolismo , Longevidade/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/microbiologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/microbiologia , Baço/patologia , Taxa de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/patologia , Tuberculose/mortalidade , Tuberculose/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
13.
Br J Ophthalmol ; 91(2): 215-8, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17020901

RESUMO

AIM: To evaluate the use of the Newcastle Control Score (NCS) in the management of intermittent exotropia (X(T)). PARTICIPANTS AND METHODS: Children aged <11 years with X(T) had an assessment of NCS as part of routine management. Other data collected included visual acuity, near and distance alignment with alternating prism cover test and near (Frisby test) and distance stereoacuity (Frisby Davis Distance Stereotest (FD2TM)). Analysis involved correlation between baseline NCS, angle and stereoacuity, examination of change over time and logistic regression to determine predictors of surgery. RESULTS: Baseline data were obtained on 272 children and follow-up data on 157. Mean (SD) age was 4 (1.9) years. Complete NCSs were obtained for all except one child at baseline, and all children at follow-up. At baseline, total NCS and the home control component were correlated with near stereo (r = -0.22, p<0.01 and r = -0.19, p<0.02, respectively), near alignment (r = 0.34, p<0.001 and r = 0.19, p<0.02) and distance alignment (r = 0.30, p<0.001 and r = 0.26, p<0.001). The clinic near control component was correlated with near alignment (r = 0.39, p<0.001), but not near stereoacuity, and the clinic distance control with near alignment (r = 0.16, p<0.02), distance alignment (r = 0.27, p<0.001) and distance stereoacuity (r = -0.25, p<0.03). A high (poor) NCS (> or =4) at the latest follow-up predicted surgery (p<0.001, OR 29.3, 95% CI 6.2 to 138.7). CONCLUSION: The NCS is a useful measure of the clinical severity of X(T), can be used to serially assess improvement or deterioration and is a useful tool for the management of these patients.


Assuntos
Exotropia/diagnóstico , Índice de Gravidade de Doença , Criança , Pré-Escolar , Interpretação Estatística de Dados , Exotropia/fisiopatologia , Exotropia/cirurgia , Seguimentos , Humanos , Lactente , Prognóstico , Acuidade Visual
14.
J Immunotoxicol ; 4(2): 165-9, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18958726

RESUMO

Evaluation of the immunotoxicity potential of some pharmaceuticals, including immunomodulatory chemicals and biologics, cannot be limited to testing in rodents. Thus, immune function tests have also been applied in studies with non-human primates and more recently dogs that assess various components of the immune system. These assays include TDAR responses with various immunogens, lymphocyte phenotyping, natural-killer cell activity, delayed-type hypersensitivity, and macrophage function assays. Approaches for incorporating immune function testing in non-rodent species, results from these tests, their interpretation and limitations with respect to drug safety assessment will be reviewed.

15.
Arch Ophthalmol ; 123(3): 356-62, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15767478

RESUMO

OBJECTIVE: To assess the intraobserver and interobserver reliability of recording uniocular fields of fixation using a modified perimeter technique in healthy subjects and patients with Graves orbitopathy (GO). Patients with restrictive myopathies, particularly GO, require accurate measurement of monocular excursions. These ductions are recorded in 4 to 12 directions of gaze using a perimeter, producing a plot known as a uniocular field of fixation. While 4 direction plots give limited information on vertical muscles, recording 12 directions is time consuming and uncomfortable. This modified technique uses the 6 directions of gaze corresponding to the primary field of action of each muscle. METHODS: A single observer measured modified uniocular fields of fixation in 35 healthy subjects aged 20 to 60 years to establish normal and age-related ranges for all ductions. Fifteen subjects underwent measurement on 5 separate occasions by the same observer to establish intraobserver reproducibility. A second observer independently performed measurements in 10 of the subjects to determine interobserver reproducibility. Reliability was compared with that measured in 29 patients with GO. RESULTS: The technique was reproducible to within 4 degrees for healthy subjects undergoing assessment by a single observer. When results of 2 observers were compared, the coefficient of repeatability was 7.9 degrees . For subjects with GO, however, maximal variability was 7.8 degrees . For clinical purposes, only a change of 8 degrees or more can be assumed to be significant. CONCLUSIONS: This technique offers advantages for assessing any restrictive myopathy, including GO to within 8 degrees . This level of accuracy is likely to be similar in other centers, and has implications for interpreting GO outcome measures, where 5 degrees was previously taken to represent significant change.


Assuntos
Fixação Ocular/fisiologia , Doença de Graves/fisiopatologia , Músculos Oculomotores/fisiopatologia , Testes de Campo Visual/métodos , Campos Visuais/fisiologia , Adulto , Envelhecimento/fisiologia , Movimentos Oculares/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes
16.
J Immunotoxicol ; 1(3): 201-5, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18958653

RESUMO

Immune-mediated drug hypersensitivity reactions (IDHR) are relatively rare reactions to drugs that can be observed in a limited population of patients, yet these reactions can have significant impacts on public health, clinical practice, and drug development. Despite the potentially significant impact of IDHR, research into the causes and mechanisms of action of these reactions has been limited. In order to identify and enhance potential research opportunities in IDHR, the Health and Environmental Sciences Institute (HESI) hosted a two-day workshop involving stakeholders from government, academia, and industry. Discussions focused on ways to increase IDHR research opportunities within both presently existing collaborative structures and new networks. Based on these discussions, workshop participants concluded that a volunteer organization of interested stakeholders could be established to provide for ongoing advocacy and coordination of efforts related to IDHR research. The primary objectives of such an organization would be to increase public awareness of the impact of IDHR, encourage multidisciplinary IDHR research and training, encourage the development and funding of IDHR research network and seed grants, and to establish a framework for the further exchange and dissemination of IDHR information.

17.
J Allergy Clin Immunol ; 109(3): S461-78, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11897992

RESUMO

Immune-mediated drug hypersensitivity reactions (IDHR) have a significant impact on clinical practice, drug development, and public health. However, research to understand IDHR mechanisms and to develop diagnostic and predictive tests has been limited. To stimulate more research, a task force with representatives from the key stakeholders (research clinicians, regulatory scientists, and immunotoxicologists from the pharmaceutical industry) was assembled to identify critical data gaps and opportunities and to make recommendations on how to overcome some of the barriers to IDHR research and address research needs. It is hoped that this report will act as a springboard for future discussions and progress toward increased funding and development of organizational structures for IDHR research.


Assuntos
Hipersensibilidade a Drogas/prevenção & controle , Hipersensibilidade a Drogas/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Avaliação das Necessidades , Pesquisa , Desenho de Fármacos , Hipersensibilidade a Drogas/imunologia , Diretrizes para o Planejamento em Saúde , Humanos
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