RESUMO
The aim of this study was to determine whether the lactones dehydroleucodine, xanthatin and 3-benzyloxymethyl-5H-furan-2-one, would be effective in an animal model of gastric ulcer induced by mast cell activation. Rats were divided into ten groups. Treatments were repeated for four days. The degree of gastric erosion was assessed with a scoring system and histological preparations. Gastric mast cell morphology was analyzed by histological procedures. Serum serotonin levels were determined as markers of mast cell activation. Statistical analyses were done using ANOVA and Tukey-Kramer test. We demonstrated that the repeated administration of compound 48/80 results in extensive mucosal lesions in the gastric mucosa and that such lesions occurred in association with mast cell degranulation and a significant increase of serum serotonin. We showed that these lesions were prevented by dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one and that this effect was similar to that obtained with sodium cromoglycate. In conclusion, the results of the present study indicate that the optimal gastric cytoprotective dose of dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one is efficacious in an animal model of gastric ulcer induced by mast cell activation. Our findings suggest that these lactones could be valuable tools for designing novel therapeutic agents for digestive disorders associated with inappropriate mast cell activation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Mastocitose/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Furanos/farmacologia , Mucosa Gástrica/patologia , Humanos , Lactonas/farmacologia , Mastocitose/metabolismo , Mastocitose/patologia , Ratos , Sesquiterpenos/farmacologia , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
Mast cell tumor is the most common skin tumor in dogs. Due to mast cell proliferation, the affected animals present clinical symptoms compatible with the release of excess histamine granules present inside these cells leading to changes in the gastrointestinal and vascular tracts with the possibility of causing anaphylactic shock. The diagnosis is made by cytopathological analysis and classified by means of histopathology. Treatment is based on staging, surgical exeresis with antineoplastic chemotherapy and drug treatment to inhibit the effects of histamine release. A dog of 14 years old of Boxer breed was attend complaining of nodulation in the testicular bag with a two month evolution. Animal was diagnosed with mast cell tumor. Treatment was instituted by surgical excision and due to the metastatic possibility in regional lymph node, antineoplastic and drug therapy was indicated, which was not successful due of the person responsible non-adherence to the treatment. Mast cell tumor classified as high grade after histopathological analysis. Animal survived for two months after diagnosis of the disease. Due to the high grade of neoplastic presentation and difficulty in treatment, the animal had low survival, corroborating with data described in the literature regarding the poor prognosis of this tumor type.
Assuntos
Masculino , Animais , Cães , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Mastocitose/diagnóstico , Mastocitose/tratamento farmacológico , Mastocitose/veterinária , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/veterináriaRESUMO
Mast cell tumor is the most common skin tumor in dogs. Due to mast cell proliferation, the affected animals present clinical symptoms compatible with the release of excess histamine granules present inside these cells leading to changes in the gastrointestinal and vascular tracts with the possibility of causing anaphylactic shock. The diagnosis is made by cytopathological analysis and classified by means of histopathology. Treatment is based on staging, surgical exeresis with antineoplastic chemotherapy and drug treatment to inhibit the effects of histamine release. A dog of 14 years old of Boxer breed was attend complaining of nodulation in the testicular bag with a two month evolution. Animal was diagnosed with mast cell tumor. Treatment was instituted by surgical excision and due to the metastatic possibility in regional lymph node, antineoplastic and drug therapy was indicated, which was not successful due of the person responsible non-adherence to the treatment. Mast cell tumor classified as high grade after histopathological analysis. Animal survived for two months after diagnosis of the disease. Due to the high grade of neoplastic presentation and difficulty in treatment, the animal had low survival, corroborating with data described in the literature regarding the poor prognosis of this tumor type.(AU)
Assuntos
Animais , Masculino , Cães , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Mastocitose/diagnóstico , Mastocitose/veterinária , Mastocitose/tratamento farmacológico , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/veterináriaRESUMO
The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.
Assuntos
Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Transtornos Mieloproliferativos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos de Anilina/uso terapêutico , Carbazóis/uso terapêutico , Dasatinibe/uso terapêutico , Eosinofilia/tratamento farmacológico , Furanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Harringtoninas/uso terapêutico , Mepesuccinato de Omacetaxina , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mastocitose/tratamento farmacológico , Nitrilas/uso terapêutico , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Quinolinas/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Varíola/tratamento farmacológico , Trombocitemia Essencial/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty-seven client-owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Lomustina/uso terapêutico , Mastocitose/veterinária , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Doenças do Cão/genética , Cães , Esquema de Medicação/veterinária , Quimioterapia Combinada , Feminino , Indóis/administração & dosagem , Lomustina/administração & dosagem , Masculino , Mastocitose/tratamento farmacológico , Mastocitose/genética , Reação em Cadeia da Polimerase/veterinária , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/administração & dosagemRESUMO
Presentación de un caso clínico en el que la terapia con dasatinib y la quimioterapia se asociaron con supervivencia a largo plazo en un paciente de 51 años, diagnosticado con mastocitosis sistémica y un mal pronóstico inicial.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Mastocitose/complicações , Mastocitose/tratamento farmacológico , Mastocitose/terapiaRESUMO
Mast cell tumor (MCT) is one of the most prevalent neoplasms that affect the skin and soft tissue of dogs. Because mast cell tumors present a great variety of clinical appearance and behavior, their treatment becomes a challenge. While retinoids are well recognized as promising antitumor agents, there have been only a few reports about retinoids' effect on canine cancers. The aim of this study was to investigate the chemosensitivity of MCT grades II and III to all-trans retinoic acid (ATRA). Immediately after surgical resection, MCT were prepared for primary culture. Samples of MCTs were also fixed in formalin for histopathology and grading according to the classification of Patnaik et al. (Veterinary Pathology 21(5):469-474, 1984). The best results were obtained when neoplastic mast cells were co-cultivated with fibroblasts. Cultured mast cells were, then, treated with concentrations of 10(-4) to 10(-7) M of ATRA, in order to evaluate their chemosensitivity to this retinoid. MTT assay was performed to estimate cell growth and death. The highest level of mast cell chemosensivity was obtained at the dose of 10(-4) M (p < 0,002). MCT of grades II or III were equally susceptible to the treatment with ATRA. Cell death was observed on the first 24 h until 48 h. According to these results, ATRA may be a potential chemotherapeutic agent for the treatment of canine MCT.
Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Mastócitos/patologia , Mastocitose/veterinária , Tretinoína/farmacologia , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doenças do Cão/patologia , Cães , Relação Dose-Resposta a Droga , Feminino , Masculino , Mastocitose/tratamento farmacológico , Mastocitose/patologia , Sais de Tetrazólio/química , Tiazóis/química , Tretinoína/administração & dosagem , Células Tumorais CultivadasRESUMO
La telangiectasia macularis eruptiva perstans (TMEP) es una variedad clínica poco frecuente de mastocitosis que afecta sólo la piel. En la literatura se encuentran descripciones de asociaciones de esta patología con otras enfermedades, como en algunos de los casos aquí descriptos. Presentamos 5 pacientes con esta patología estudiados en el Servicio de Dermatología del Hospital Córdoba, en el lapso de dos años (2003-2004) (AU)
Assuntos
Humanos , Masculino , Adulto , Feminino , Criança , Pessoa de Meia-Idade , Mastocitose/diagnóstico , Mastocitose/patologia , Mastocitose/tratamento farmacológico , Dermatite Alérgica de Contato/complicações , Policitemia Vera/complicações , Dor Abdominal/complicações , Sífilis/complicações , Telangiectasia/diagnóstico , Telangiectasia/etiologiaRESUMO
La telangiectasia macularis eruptiva perstans (TMEP) es una variedad clínica poco frecuente de mastocitosis que afecta sólo la piel. En la literatura se encuentran descripciones de asociaciones de esta patología con otras enfermedades, como en algunos de los casos aquí descriptos. Presentamos 5 pacientes con esta patología estudiados en el Servicio de Dermatología del Hospital Córdoba, en el lapso de dos años (2003-2004) (AU)
Assuntos
Humanos , Masculino , Adulto , Feminino , Criança , Pessoa de Meia-Idade , Mastocitose/diagnóstico , Mastocitose/patologia , Mastocitose/tratamento farmacológico , Dermatite Alérgica de Contato/complicações , Policitemia Vera/complicações , Dor Abdominal/complicações , Sífilis/complicações , Telangiectasia/diagnóstico , Telangiectasia/etiologiaRESUMO
La telangiectasia macularis eruptiva perstans (TMEP) es una forma de mastocitosis cutánea poco frecuente, que se manifiesta casi exclusivamente en adultos. Su diagnóstico es básicamente clínico y no se dispone hasta la actualidad de una terapéutica específica eficaz. Se presentan cuatro pacientes de sexo masculino, edad promedio de 54 años, con manifestaciones clínicas e histológicas de TMEP, en diferentes períoddos de evolución. Todos presentaron patología úlcero éptica, asociación frecuente de las mastocitosis cutáneas. Objetivo: Presentación clínica de una forma poco frecuente de mastocitosis cutánea y revisión de la bibliografía