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1.
Acta Derm Venereol ; 101(9): adv00544, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34436621

RESUMO

Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechlorethamine, is a topical chemotherapeutic, which has been in use for over 60 years. In 2013, the US Food and Drug Administration approved chlormethine/mechlorethamine gel (Valchlor®) for treatment of stage IA and IB mycosis fungoides. Chlormethine/mechlorethamine gel is an effective therapy; however, its use may be limited by the development of adverse cutaneous reactions. Off-label dosing modifications, as well as co-administration of topical steroids and an aggressive moisturization regimen, can be used to reduce these side-effects. We report here 4 cases of mycosis fungoides treated with chlormethine/mechlorethamine gel at the Comprehensive Skin Cancer Center at Columbia University Irving Medical Center, which provide insights into the use of this therapy in clinical practice.


Assuntos
Micose Fungoide , Neoplasias Cutâneas , Antineoplásicos Alquilantes , Humanos , Mecloretamina/efeitos adversos , Micose Fungoide/diagnóstico , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Universidades
2.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072833

RESUMO

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male-female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-ß (TGF-ß) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-ß and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.


Assuntos
Colágeno/genética , Proteínas de Choque Térmico HSP90/genética , Fibrose Pulmonar Idiopática/genética , Fator de Crescimento Transformador beta/genética , Animais , Feminino , Regulação da Expressão Gênica/genética , Humanos , Ácido Clorídrico/toxicidade , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mecloretamina/toxicidade , Camundongos , Proteínas Smad/genética
4.
Toxicol Appl Pharmacol ; 423: 115569, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33971176

RESUMO

Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Histonas/biossíntese , Ativação de Macrófagos/efeitos dos fármacos , Mecloretamina/toxicidade , MicroRNAs/biossíntese , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Expressão Gênica , Histonas/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Ativação de Macrófagos/fisiologia , Masculino , Camundongos , MicroRNAs/genética , Ratos , Ratos Wistar
5.
Adv Ther ; 38(6): 3455-3464, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33928511

RESUMO

INTRODUCTION: Chlormethine gel is a skin-directed therapy recommended for patients with early-stage mycosis fungoides (MF) cutaneous T cell lymphoma. METHODS: Herein, we present three cases of patients with stage IB-IIB MF who were treated with chlormethine gel and concomitant therapies. RESULTS: All patients responded well to treatment with chlormethine gel; complete responses were observed with improvements in Modified Severity-Weighted Assessment Tool scores and severity of lesions; one patient reported an improvement in quality of life. While adverse events did occur after treatment initiation, they were skin related and could be effectively managed through reductions in treatment frequency and the addition of emollients and topical steroids. CONCLUSION: The cases presented here illustrate that chlormethine gel is an effective and safe treatment option for patients with MF who had received prior therapies that had proved ineffective. Chlormethine gel could be combined with other skin-directed or systemic therapies for optimal benefit. Incidences of dermatitis were seen to be successfully managed and quality of life benefits were also reported.


Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , Mecloretamina , Micose Fungoide/tratamento farmacológico , Qualidade de Vida , Neoplasias Cutâneas/tratamento farmacológico
6.
Am J Clin Dermatol ; 22(3): 407-414, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33656660

RESUMO

BACKGROUND: Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking. OBJECTIVE: Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting. METHODS: This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA-IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire. RESULTS: In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores. CONCLUSIONS: This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mecloretamina/administração & dosagem , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Administração Oral , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Seguimentos , Géis , Humanos , Masculino , Mecloretamina/efeitos adversos , Pessoa de Meia-Idade , Micose Fungoide/diagnóstico , Micose Fungoide/psicologia , Estadiamento de Neoplasias , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/psicologia , Resultado do Tratamento , Estados Unidos
7.
Int J Radiat Oncol Biol Phys ; 110(2): 444-451, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385495

RESUMO

PURPOSE: Combined modality therapy (CMT) is standard therapy for early-stage Hodgkin lymphoma (ESHL). We previously reported excellent outcomes with the abbreviated Stanford V regimen. Herein we report updated results with median follow-up >10 years on survival, therapy-related late effects, and impact of disease risk factors on patient outcomes. METHODS AND MATERIALS: The G4 and G5 studies enrolled patients with stage I-IIA nonbulky ESHL. Patients received 8 weeks of Stanford V chemotherapy followed by 30 Gy modified involved-field radiation therapy (mIFRT) (G4) or Stanford V-C + 20 Gy mIFRT (G5). Patients were categorized as favorable or unfavorable risk per German Hodgkin Study Group (GHSG) criteria and outcomes between groups compared. RESULTS: A total of 129 patients were enrolled (68 favorable and 61 unfavorable risk). In the G4 study (n = 87), at median follow-up of 19.7 years, 5-, 10-, and 15-year progression-free survival (PFS) and overall survival (OS) were 95.4%/97.7%, 91.8%/96.5%, and 91.8%/95.3%, respectively. In the G5 study (n = 42), at median follow-up of 13.5 years, the 5-, 10-, and 15-year PFS and OS were 92.9%/100%, 92.9%/100%, and 88.4%/91.9%, respectively. PFS (P = .86) and OS (P = .86) were not significantly different between studies. There were also no significant differences between studies in patients with favorable or unfavorable risk for PFS (F: P = .53; U: P = .96), OS (F: P = .99; U: P = .78), secondary malignancies (F: P = .74; U: P = 1.0), and cardiovascular complications (F: no cases; U: P = 1.0). CONCLUSIONS: The G4 and G5 studies achieve high rates of durable remission; 20 versus 30 Gy mIFRT and cyclophosphamide substituted for mechlorethamine did not compromise nodal control, PFS, or OS in both favorable and unfavorable risk disease. These results support the efficacy of CMT in early-stage disease and lower-dose radiation therapy in patients with favorable and nonbulky unfavorable ESHL.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Terapia Combinada/métodos , Ciclofosfamida/uso terapêutico , Substituição de Medicamentos , Feminino , Seguimentos , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Mecloretamina/uso terapêutico , Pessoa de Meia-Idade , Segunda Neoplasia Primária , Intervalo Livre de Progressão , Dosagem Radioterapêutica , Indução de Remissão , Fatores de Risco , Terapia de Salvação/métodos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
Biochem J ; 477(23): 4543-4558, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175093

RESUMO

Nitrogen mustards are among the first modern anticancer chemotherapeutics that are still widely used as non-specific anticancer alkylating agents. While the mechanism of action of mustard drugs involves the generation of DNA interstrand cross-links, the predominant lesions produced by these drugs are nitrogen half-mustard-N7-dG (NHMG) adducts. The bulky major groove lesion NHMG, if left unrepaired, can be bypassed by translesion synthesis (TLS) DNA polymerases. However, studies of the TLS past NHMG have not been reported so far. Here, we present the first synthesis of an oligonucleotide containing a site-specific NHMG. We also report kinetic and structural characterization of human DNA polymerase η (polη) bypassing NHMG. The templating NHMG slows dCTP incorporation ∼130-fold, while it increases the misincorporation frequency ∼10-30-fold, highlighting the promutagenic nature of NHMG. A crystal structure of polη incorporating dCTP opposite NHMG shows a Watson-Crick NHMG:dCTP base pair with a large propeller twist angle. The nitrogen half-mustard moiety fits snugly into an open cleft created by the Arg61-Trp64 loop of polη, suggesting a role of the Arg61-Trp64 loop in accommodating bulky major groove adducts during lesion bypass. Overall, our results presented here to provide first insights into the TLS of the major DNA adduct formed by nitrogen mustard drugs.


Assuntos
Adutos de DNA/química , DNA Polimerase Dirigida por DNA/química , Mecloretamina/química , Oligonucleotídeos/química
10.
Reprod Toxicol ; 98: 252-259, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33164761

RESUMO

Oocytes are vulnerable to alkylating agents like nitrogen mustard (NM), which can cause mitochondrial dysfunction associated with increased oxidative stress. Because mitochondria are maternally inherited, NM exposure affects oocyte mitochondrial physiology and compromises future progeny. Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux such cytotoxic substances; MDR-1 is expressed in oocyte plasma and mitochondrial membranes and protects against oxidative stress. Our objective was to investigate how loss of MDR-1 can modulate oocyte response to NM transgenerationally. Wild Type (WT) and Mdr1a mutant female mice were injected intraperitoneally with sterile saline (control) or 0.1 mg/kg NM. 48 h post-injection, females were either sacrificed for F0 studies or mated with control males to yield F1 pups. After weaning, F1 females were sacrificed or mated to yield F2 pups. Germinal vesicle oocytes were assessed for mitochondrial membrane potential and reactive oxygen species (ROS) levels. NM exposed oocytes of both genotypes exhibited significantly higher ROS than controls in F0 and F1. NM F2 oocytes of neither genotype exhibited significantly higher ROS, though variation in Mdr1a mutants led to an upward trend. NM oocytes of both genotypes exhibited significantly disrupted mitochondrial membrane potential in F0. WT regained normalcy by F1 whereas Mdr1a mutants were unable to by F2. Our data suggest that Mdr1a mutants exhibit transgenerational mitochondrial dysfunction following toxic challenge that persists, implying that MDR-1 protects against toxicant-induced mitochondrial stress. Women without functional MDR-1 exposed to environmental toxicants could therefore be at risk for passing on compromised mitochondria to future offspring.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Substâncias para a Guerra Química/toxicidade , Mecloretamina/toxicidade , Mitocôndrias/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Feminino , Mutação com Perda de Função , Masculino , Troca Materno-Fetal , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/fisiologia , Oócitos/metabolismo , Oócitos/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Ann N Y Acad Sci ; 1480(1): 246-256, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33165947

RESUMO

Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophage-dominant inflammatory response and the production of proinflammatory/profibrotic mediators, including tumor necrosis factor alpha (TNF-α). Herein, we refined magnetic resonance imaging (MRI) and computed tomography (CT) imaging methodologies to track the progression of NM-induced lung injury in rodents and assess the efficacy of anti-TNF-α antibody in mitigating toxicity. Anti-TNF-α antibody was administered to rats (15 mg/kg, every 8 days, intravenously) beginning 30 min after treatment with phosphate-buffered saline control or NM (0.125 mg/kg, intratracheally). Animals were imaged by MRI and CT prior to exposure and 1-28 days postexposure. Using MRI, we characterized acute lung injury and fibrosis by quantifying high-signal lung volume, which represents edema, inflammation, and tissue consolidation; these pathologies were found to persist for 28 days following NM exposure. CT scans were used to assess structural components of the lung and to register changes in tissue radiodensities. CT scans showed that in control animals, total lung volume increased with time. Treatment of rats with NM caused loss of lung volume; anti-TNF-α antibody mitigated this decrease. These studies demonstrate that MRI and CT can be used to monitor lung disease and the impact of therapeutic intervention.


Assuntos
Lesão Pulmonar Aguda , Anticorpos Monoclonais Murinos/farmacologia , Irritantes/envenenamento , Imageamento por Ressonância Magnética , Mecloretamina/envenenamento , Fibrose Pulmonar , Tomografia Computadorizada por Raios X , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Ratos , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
12.
Ann N Y Acad Sci ; 1480(1): 170-182, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32892377

RESUMO

Injury of the skin from exposure to toxic chemicals leads to the release of inflammatory mediators and the recruitment of immune cells. Nitrogen mustard (NM) and other alkylating agents cause severe cutaneous damage for which there are limited treatment options. Here, we show that combined treatment of vitamin D3 (VD3) and spironolactone (SP), a mineralocorticoid receptor antagonist, significantly improves the resolution of inflammation and accelerates wound healing after NM exposure. SP enhanced the inhibitory effect of VD3 on nuclear factor-kB activity. Combined treatment of NM-exposed mice with VD3 and SP synergistically inhibited the expression of iNOS in the skin and decreased the expression of matrix metallopeptidase-9, C-C motif chemokine ligand 2, interleukin (IL)-1α, and IL-1ß. The combined treatment decreased the number of local proinflammatory M1 macrophages resulting in an increase in the M2/M1 ratio in the wound microenvironment. Apoptosis was also decreased in the skin after combined treatment. Together, this creates a proresolution state, resulting in more rapid wound closure. Combined VD3 and SP treatment is effective in modulating the immune response and activating anti-inflammatory pathways in macrophages to facilitate tissue repair. Altogether, these data demonstrate that VD3 and SP may constitute an effective treatment regimen to improve wound healing after NM or other skin chemical injury.


Assuntos
Colecalciferol/farmacologia , Mecloretamina/toxicidade , Pele , Espironolactona/farmacologia , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Animais , Apoptose/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Células RAW 264.7 , Pele/lesões , Pele/metabolismo , Pele/patologia , Ferimentos e Lesões/induzido quimicamente , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
13.
Ann N Y Acad Sci ; 1480(1): 146-154, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32767459

RESUMO

Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1ß. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity.


Assuntos
Substâncias para a Guerra Química/envenenamento , Regulação da Expressão Gênica/efeitos dos fármacos , Lesão Pulmonar/metabolismo , Macrófagos Alveolares/metabolismo , Mecloretamina/envenenamento , RNA-Seq , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Wistar
14.
Anal Methods ; 12(36): 4447-4456, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32856667

RESUMO

The development and optimization of an analytical method for the detection and identification of reactive metabolite of organochlorine chemical warfare agent nitrogen mustards (NMs), 2-[(2-chloroethyl)(alkyl)amino]ethanol (CEAAE), known as half nitrogen mustard, in blood samples is presented, herein. In this study, half nitrogen mustards in plasma are presented as a new and unambiguous biomarker of NM exposure since the fully hydrolyzed product, i.e., amino alcohols, are common industrial chemicals that can be present as such without getting exposed to NMs. Thus, the detection of half nitrogen mustard as a biomarker holds great significance for verification by the Chemical Weapon Convention (CWC) and will also be helpful in understanding the pharmacokinetics of NM-based chemotherapeutic pro-drugs. To the best of our knowledge, this is the first report on the detection of half nitrogen mustards in any matrice, including plasma. A very simple sample preparation protocol was developed for its extraction from plasma samples. Heptafluorobutyrylation and gas chromatography-tandem mass spectrometry in the positive chemical ionization mode were developed for the detection and identification of halfNMs. The developed method has shown excellent analytical figures of merits such as a wide range of linearity (1.0-50 ng mL-1), low limit of detection (0.3-0.5 ng mL-1), and low limit of quantification (1.0 ng mL-1). The interday and intraday reproducibilities were also less than 15%. The developed method was successfully applied to real-world samples; in vitro human plasma was spiked with ∼1 ng mL-1 of all the NMs and in vivo studies were done with rats intravenously exposed to 1 × LD50 of bis(2-chloroethyl)methylamine (HN2).


Assuntos
Mecloretamina , Compostos de Mostarda Nitrogenada , Animais , Biomarcadores , Cromatografia Gasosa-Espectrometria de Massas , Mecloretamina/toxicidade , Ratos , Espectrometria de Massas em Tandem
15.
J Drugs Dermatol ; 19(8): 803-805, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32845598

RESUMO

Langerhans cell histiocytosis (LCH) limited to the skin is rare in adult patients. Given the challenges of prospective clinical trials for this rare disease, there is paucity in data to guide the management of cutaneous LCH. Topical nitrogen mustard is a possible treatment for cutaneous LCH with positive responses in five known adult cases in the literature. In this report, we present two adult patients with recalcitrant cutaneous LCH and no evidence of systemic involvement who had rapid and complete response on topical nitrogen mustard therapy. We provide support for topical nitrogen mustard as a treatment option for primary cutaneous LCH which may spare patients from requiring systemic immunosuppressive treatments. J Drugs Dermatol. 2020;19(8):803-805. doi:10.36849/JDD.2020.4943.


Assuntos
Alquilantes/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Mecloretamina/administração & dosagem , Dermatopatias/tratamento farmacológico , Administração Cutânea , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/patologia , Humanos , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/diagnóstico , Dermatopatias/patologia , Resultado do Tratamento
16.
J Chromatogr A ; 1625: 461306, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709349

RESUMO

A pentafluorobenzoylation (PFBz)-liquid chromatography-tandem mass spectrometry method was developed for qualitative and quantitative analysis of ethanolamines (EAs, nitrogen mustard degradation products). With this method, highly hydrophilic EAs can be sufficiently analyzed with a commonly used reversed phase column (retention times: (PFBz)2-methyl diethanolamine, 9.1 min; (PFBz)2-ethyl diethanolamine, 9.8 min; and (PFBz)3-triethanolamine, 17.6 min). The applicability of the method for real samples was investigated via recovery tests. Methyl diethanolamine and ethyl diethanolamine were detected at concentrations as low as 1 ng/mL in serum and 10 ng/mL in urine, and quantified within the range of 1-1000 ng/mL and 10-1000 ng/mL, respectively.


Assuntos
Cromatografia Líquida/métodos , Fluorbenzenos/química , Mecloretamina/análise , Espectrometria de Massas em Tandem/métodos , Etanolamina/sangue , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção
17.
Ann N Y Acad Sci ; 1480(1): 5-13, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32725637

RESUMO

Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.


Assuntos
Substâncias para a Guerra Química/envenenamento , Suplementos Nutricionais , Irritantes/envenenamento , Mecloretamina/envenenamento , Gás de Mostarda/envenenamento , Fibrose Pulmonar , Animais , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/dietoterapia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
18.
Int J Mol Sci ; 21(13)2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32635192

RESUMO

Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-ß, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/prevenção & controle , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Resorcinóis/farmacologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Mecloretamina/antagonistas & inibidores , Mecloretamina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/patologia
19.
Inhal Toxicol ; 32(4): 141-154, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32362214

RESUMO

Objective: Sulfur mustards are toxic agents used as a chemical warfare in the twentieth century. Exposure to nitrogen mustards (NM), their more water-soluble analogs, is associated with respiratory, dermatological, neurological, and systemic symptoms whose severity depends on dose and length of contact. Long-term effects of acute inhalation have been related to the development of chronic lung injury and pulmonary fibrosis whose precise mechanisms and potential antidotes are yet to be discovered.Materials and methods: We have developed a model of NM-induced pulmonary fibrosis by intratracheally instilling mechlorethamine hydrochloride into C57Bl/6J male mice.Results and Discussion: Following mechlorethamine exposure, strong early and milder late inflammatory responses were observed. Initially, the number of white blood cells and levels of protein and pro-inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) increased, followed by increases in the number of macrophages and the levels of transforming growth factor-ß (TGF-ß), a pro-fibrotic mediator. Analysis of lung homogenates revealed increased phosphorylation of pro-fibrotic biomarkers, serine/threonine-selective protein kinases (p-ERK), and heat shock protein 90 (P-HSP90) at 10 and 30 days after exposure. Total collagen expression and deposition of extracellular matrix proteins also increased. Lung function measurements demonstrated the presence of both obstructive and restrictive disease in agreement with evidence of increased lower airway peribronchial collagen deposition and parenchymal fibrosis.Conclusions: We conclude that the mouse represents a useful model of NM-induced acute lung injury and chronic pulmonary fibrosis, the latter driven by the overexpression of TGF-ß, p-ERK, and P-HSP90. This model may prove useful in the pre-clinical development of antidotes and other countermeasures.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Substâncias para a Guerra Química , Modelos Animais de Doenças , Mecloretamina , Fibrose Pulmonar/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Doença Crônica , Citocinas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Fator de Crescimento Transformador beta/metabolismo
20.
Ann N Y Acad Sci ; 1479(1): 223-233, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32408394

RESUMO

Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 µM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 µM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 µM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 µM NM-exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustard-induced airway pathology.


Assuntos
Citotoxinas/toxicidade , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Pulmão/metabolismo , Mecloretamina/toxicidade , Fator A de Crescimento do Endotélio Vascular/biossíntese , Linhagem Celular , Células Endoteliais/patologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/patologia , Proteínas de Membrana/biossíntese
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