RESUMO
Gallbladder cancer is the most frequent neoplasm originating from the extrahepatic biliary tract, with characteristics of late presentation and rapid progression. We report the case of a 58 years old female patient with concomitant small cell carcinoma and adenocarcinoma of the gallbladder, incidentally reported after a cholecystectomy performed for cholelithiasis. According to the stage of the disease, we performed a second surgical procedure with laparotomy, resection of the liver parenchyma IVb and V and regional lymphadenectomy. After multidisciplinary team consultation, the patient was not administrated chemotherapy. She was well followed up at our department and she is alive 12 month after surgery.
Assuntos
Adenocarcinoma/patologia , Carcinoma de Células Pequenas/patologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias Primárias Múltiplas/patologia , Adenocarcinoma/complicações , Adenocarcinoma/cirurgia , Adenoma/complicações , Adenoma/patologia , Adenoma/cirurgia , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/cirurgia , Colecistectomia Laparoscópica , Colelitíase/complicações , Colelitíase/cirurgia , Feminino , Neoplasias da Vesícula Biliar/complicações , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Achados Incidentais , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/cirurgiaRESUMO
OBJECTIVES: To describe the efficacy and safety of different biological agents in a large cohort of 20 patients with adult-onset Still's disease (AOSD). METHOD: We retrospectively evaluated 20 patients with severe or refractory AOSD treated with at least one biological agent (anakinra, etanercept, tocilizumab, and adalimumab), followed up for at least 12 months at our Institution. We collected and analysed data on the disease course, treatment outcome, and adverse effects, and compared our data with other published series. RESULTS: The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. In eight patients the biological agent that was first administered proved ineffective, and a switch to a different biologic was necessary. In three patients a third biologic was necessary to achieve disease control. The biologics eventually determined a clinical response in all patients. Patients with systemic disease showed better responses than patients with chronic articular disease (p < 0.05). Biological agents allowed either the withdrawal or the tapering of corticosteroid therapy (p < 0.0001) and of disease-modifying anti-rheumatic agents (DMARDs; p < 0.05). Three patients experienced herpes zoster reactivation. CONCLUSIONS: This is the longest follow-up of a cohort of AOSD patients treated with biological agents. Our data show that biologics are safe and generally effective in the long-term management of AOSD, particularly in cases with systemic disease, and suggest that a clinical response can be obtained in almost all AOSD patients, although a switch to drugs with a different mechanism of action may be necessary.
Assuntos
Fatores Biológicos/efeitos adversos , Fatores Biológicos/uso terapêutico , Doença de Still de Início Tardio/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos de Coortes , Etanercepte , Feminino , Seguimentos , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Giant Condyloma Acuminatum (GCA) is a rare, slow growing, large cauliflower tumor of the penile foreskin and perianal region with benign histologic appearance but high propensity for local invasion and recurrences. GCA is associated with Human Papilloma Virus (HPV) types 6 and 11 and it also has considerable risk of neoplastic transformation into fully invasive squamous cell carcinoma into about 5 years. OBJECTIVE: Because of the rarity of perianal GCA, to date there is no general agreement on the best method for treatment. We wanted to know if surgical approach only was a good method to treat our case. CASE REPORT: A 28 years old man, HIV-negative, with a 4 years history of perianal GCA quickly growing underwent full tickness local excision at least 0,7 cm margin of normal tissue with skin grafting taken from the thighs. Fecal contamination was avoided by diet and loperamide per os. At two years follow-up no recurrence was detected. CONCLUSION: Surgical approach with full tickness excision and immediate skin-grafting and regular follow-up demonstrated effective to treat GCA and to minimize disease recurrence.
Assuntos
Neoplasias do Ânus/patologia , Tumor de Buschke-Lowenstein/patologia , Adulto , Neoplasias do Ânus/cirurgia , Tumor de Buschke-Lowenstein/cirurgia , Progressão da Doença , Humanos , Masculino , Fatores de TempoRESUMO
OBJECTIVES: To characterise the clinical phenotype of Italian patients with adult-onset Still's disease (AOSD). METHODS: Sixty-six subjects who received a definite diagnosis of AOSD were seen and followed-up at our institution from 1991 to 2009. The diagnosis was made by a senior rheumatologist and confirmed by Yamaguchi's criteria for AOSD. Data regarding clinical manifestations, laboratory and radiographic features, and disease course were collected and compared with those reported in other published series of different ethnicity. RESULTS: The most frequent features were: articular pain (100%), acute phase reactants elevation (100%), elevated serum ferritin (97%), high fever (95%), negative RF and ANA (92%), neutrophilia (82%), skin rash (79%), and overt arthritis (79%). Forty-percent of patients showed a chronic articular disease. Five subjects (8%) experienced severe, life-threatening complications, and 1 patient died. As compared to other North American, North European, Middle Eastern, and Far Eastern cohorts, Italian patients showed significant differences in several epidemiologic, clinical and laboratory features. CONCLUSIONS: Our data show that AOSD is rare in the Italian population, and that its clinical presentation appears to be significantly influenced by the ethnicity of the affected patients. Given its broad differential diagnosis, early recognition of this condition is challenging, but it could become crucial in the setting of severe complications. Beyond the protean manifestations of this disease, a clinical picture of seronegative febrile arthritis and skin rash, concurrent with a marked elevation in serum ferritin should always be mindful of AOSD.
Assuntos
Povo Asiático/estatística & dados numéricos , Doença de Still de Início Tardio/complicações , Doença de Still de Início Tardio/etnologia , População Branca/estatística & dados numéricos , Proteínas de Fase Aguda/metabolismo , Adolescente , Adulto , Idoso , Anticorpos Antinucleares/sangue , Feminino , Ferritinas/sangue , Febre/etnologia , Febre/fisiopatologia , Humanos , Itália/epidemiologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dor/etnologia , Dor/etiologia , Dor/fisiopatologia , Fator Reumatoide/sangue , Doença de Still de Início Tardio/fisiopatologia , Adulto JovemRESUMO
It has been demonstrated that the forebrain cholinergic system and the extracellular regulated kinase signal transduction pathway are involved in the mechanisms of learning, encoding, and storage of information. We investigated the involvement of the cholinergic and glutamatergic systems projecting to the medial prefrontal cortex and ventral hippocampus and of the extracellular regulated kinase signal transduction pathway in the acquisition and recall of the step-down inhibitory avoidance response in the rat, a relatively simple behavioral test acquired in a one-trial session. To this aim we studied by microdialysis the release of acetylcholine and glutamate, and by immunohistochemistry the activation of extracellular regulated kinase during acquisition, encoding and recall of the behavior. Cholinergic, but not glutamatergic, neurons projecting to the medial prefrontal cortex and ventral hippocampus were activated during acquisition of the task, as shown by increase in cortical and hippocampal acetylcholine release. Released acetylcholine in turn activated extracellular regulated kinase in neurons located in the target structures, since the muscarinic receptor antagonist scopolamine blocked extracellular regulated kinase activation. Both increased acetylcholine release and extracellular regulated kinase activation were necessary for memory formation, as administration of scopolamine and of extracellular regulated kinase inhibitors was followed by blockade of extracellular regulated kinase activation and amnesia. Our data indicate that a critical function of the learning-associated increase in acetylcholine release is to promote the activation of the extracellular regulated kinase signal transduction pathway and help understanding the role of these systems in the encoding of an inhibitory avoidance memory.
Assuntos
Acetilcolina/metabolismo , Aprendizagem da Esquiva/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Prosencéfalo/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Rememoração Mental/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Antagonistas Muscarínicos/farmacologia , Córtex Pré-Frontal/metabolismo , Prosencéfalo/metabolismo , Ratos , Ratos Wistar , Escopolamina/farmacologiaRESUMO
PURPOSE: Dirofilaria repens infection is the most frequent and widespread dirofilariasis in the world. In Italy subcutaneous dirofilariasis is present especially in Northern-Central areas. METHODS: A woman with a palpebral lump is presented. RESULTS: After subcutaneous and muscular décollement, the authors found and removed a parasite. The final diagnosis was subcutaneous parasitosis due to D. repens. CONCLUSIONS: Surgery was both diagnostic and therapeutic.
Assuntos
Dirofilariose/parasitologia , Infecções Oculares Parasitárias/parasitologia , Doenças Palpebrais/parasitologia , Adulto , Animais , Diagnóstico Diferencial , Dirofilaria/isolamento & purificação , Dirofilariose/diagnóstico , Dirofilariose/cirurgia , Infecções Oculares Parasitárias/diagnóstico , Infecções Oculares Parasitárias/cirurgia , Doenças Palpebrais/diagnóstico , Doenças Palpebrais/cirurgia , Feminino , HumanosAssuntos
Cognição/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/análogos & derivados , Histamina/farmacologia , Animais , Injeções Intraventriculares , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pirilamina/farmacologia , Ratos , Ratos Wistar , Estimulação QuímicaAssuntos
Aminas , Anticonvulsivantes/farmacologia , Química Encefálica/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos , Histamina/metabolismo , Ácido gama-Aminobutírico , Acetatos/farmacologia , Animais , Etossuximida/farmacologia , Gabapentina , Metilistaminas/metabolismo , Fenitoína/farmacologia , Ratos , Ratos WistarRESUMO
Tyrosine phosphorylation is controlled by a balance of tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Whereas the contribution of PTKs to breast tumorigenesis is the subject of intense scrutiny, the potential role of PTPs is poorly known. RPTPalpha is implicated in the activation of Src family kinases, and regulation of integrin signaling, cell adhesion, and growth factor responsiveness. To explore its potential contribution to human neoplasia, we surveyed RPTPalpha protein levels in primary human breast cancer. We found RPTPalpha levels to vary widely among tumors, with 29% of cases manifesting significant overexpression. High RPTPalpha protein levels correlated significantly with low tumor grade and positive estrogen receptor status. Expression of RPTPalpha in breast carcinoma cells led to growth inhibition, associated with increased accumulation in G0 and G1, and delayed tumor growth and metastasis. To our knowledge, this is the first example of a study correlating expression level of a specific bona fide PTP with neoplastic disease status in humans.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Proteínas Tirosina Fosfatases/biossíntese , Receptores de Superfície Celular , Animais , Neoplasias da Mama/genética , Divisão Celular/fisiologia , Feminino , Amplificação de Genes , Humanos , Neoplasias Mamárias Experimentais/enzimologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores , Células Tumorais CultivadasRESUMO
The aim of this study was to elucidate the effect caused by the inhibition of histamine catabolism by means of metoprine and the activation of histamine H(1) receptors by selective agonists on learning and memory processes, using a modified method of the mouse passive avoidance test. The administration of scopolamine 1 mg/kg (i. p.) immediately after the training session caused statistically-significant amnesia during the retention trial performed 24 h later. Piracetam (30 mg/kg (i.p.)), used as a positive control, and administered 20 min before the training session, prevented scopolamine-induced memory impairment. The histamine-N-methyltransferase inhibitor, metoprine, (2 and 5 mg/kg (s.c.)) had effects similar to those of this nootropic drug. The highly-selective H(1) receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 microg/mouse (i.c.v.)) and the less selective agonist, 2-thiazolylethylamine (2-TEA) (0.1 and 0.3 microg/mouse (i.c.v.)) both antagonized the scopolamine-induced amnesia significantly and in a dose-related manner. The selective H(1) receptor antagonist, pyrilamine (20 mg/kg (i.p.)), revealed no effect by itself, but significantly prevented the antiamnesic action both that of the H(1) receptor agonists, and that of endogenous histamine, released by metoprine, thus suggesting a cognitive improvement via the activation of H(1) receptors.
Assuntos
Amnésia/tratamento farmacológico , Aprendizagem da Esquiva/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/análogos & derivados , Pirimetamina/análogos & derivados , Amnésia/induzido quimicamente , Animais , Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina N-Metiltransferase/antagonistas & inibidores , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Antagonistas Muscarínicos , Nootrópicos/farmacologia , Piracetam/farmacologia , Pirilamina/farmacologia , Pirimetamina/farmacologia , Receptores Histamínicos H1/fisiologia , Escopolamina , Tiazóis/farmacologiaRESUMO
We evaluated the effect of tamoxifen (TAM) on tumor development in proto-neu transgenic mice that spontaneously develop mammary carcinomas overexpressing the neu protein. These mammary carcinomas are hormone independent because superimposable growth of transplants was observed in females and males. Virgin transgenic mice treated with TAM from 24 weeks of age, ie., when subclinical mammary tumors are already present, showed a slightly accelerated tumor development. In contrast, transgenic mice treated with TAM starting at 12 weeks of age, when subclinical tumors are not yet present, showed a 50% reduction of tumor incidence. Light microscopy analysis of the mammary gland of these mice revealed an apparently normal ductal branching but a complete regression of the acini. In conclusion, TAM can prevent the occurrence of hormone-independent breast carcinoma if given early enough to inhibit normal cells.
Assuntos
Anticarcinógenos/uso terapêutico , Genes erbB-2 , Neoplasias Mamárias Experimentais/prevenção & controle , Receptor ErbB-2/fisiologia , Tamoxifeno/uso terapêutico , Animais , Feminino , Masculino , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , Regiões Promotoras GenéticasRESUMO
In this study we investigated the immunochemical and cytochemical reactivity of two monoclonal antibodies against the 16-amino acid tandem repeat of MUC4 to demonstrate a possible variation of the mucin core peptide expression related to lung cancer. The immunocytochemical anti-MUC4 reactivity was analyzed in four lung cancer cell lines (Calu-1, Calu-3, H460, SKMES) and in other tumor cell lines, as well as in frozen materials from 21 lung adenocarcinomas (ACs), including five bronchioloalveolar carcinomas (BACs), and 11 squamous cell lung carcinomas (SqCCs). A weak fluorescence anti-MUC4 positivity (range: 10.3-16.2) was observed only in acetone-fixed lung cancer cell lines Calu-1, Calu-3 and H460. These three lung cancer cell lines also showed a cytoplasmic immunoperoxidase reactivity. The immunostaining in lung cancer tissues showed a granular cytoplasmic reactivity: 15/21 (71%) and 17/21 (80%) ACs were positive with BC-LuC18.2 and BC-LuCF12, respectively. All BACs were positive. Moderate to strong reactivity was present in well-differentiated ACs. In the normal lung parenchyma counterparts weak reactivity was found only in bronchiolar cells. All SqCCs were negative. Anti-MUC4 reactivity was also observed in the alveolar mucus. In conclusion, our anti-MUC4 MAbs detect a secretion product present in mucus and this product is elaborated by lung cancer cells and overexpressed in well-differentiated lung ACs.
Assuntos
Adenocarcinoma Bronquioloalveolar/imunologia , Adenocarcinoma/imunologia , Antígenos de Neoplasias/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , Mucinas/imunologia , Adenocarcinoma/patologia , Adenocarcinoma Bronquioloalveolar/patologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais , Carcinoma de Células Escamosas/patologia , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mucina-4 , Proteínas de Neoplasias/imunologia , Sequências de Repetição em Tandem , Células Tumorais CultivadasRESUMO
The high-affinity nerve growth factor receptor corresponds to the tyrosine protein kinase encoded by the proto-oncogene trkA. Different findings suggest that nerve growth factor (NGF) can be operative in the growth modulation of tumor cell lines possessing high-affinity binding sites for this molecule. Using as immunizing material the SKNBE neuroblastoma cell line transfected with proto-trkA we produced a monoclonal antibody (MAb) able to recognize the high-affinity nerve growth factor receptor. The selected MAb, designated MGR12, is directed against an epitope present on the extracellular domain of the receptor since it showed reactivity on living trkA-expressing cells and was able to immunoprecipitate the proto-trkA molecule. The MGR12 MAb is directed against a non-functional epitope since it neither inhibited NGF binding nor induced receptor internalization. This new reagent appears to be an appropriate tool for analyzing the expression of high-affinity nerve growth factor receptor in tumors of different origin and for elucidating its involvement in tumor progression.
Assuntos
Anticorpos Monoclonais , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores de Fator de Crescimento Neural/imunologia , Células 3T3 , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Imunoeletrônica , Proto-Oncogene Mas , Receptor trkA , Células Tumorais CultivadasRESUMO
The synthesis of new 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2, 4]benzotriazine 5-oxides and their binding activities at the central benzodiazepine receptor (BZR) are reported. The derivatives substituted at the 3-position with electron-rich five-membered rings, such as pyrrole 11, 2-thiophene 13c, or 3-thiophene 13d, showed good affinity values for BZR. In in vivo tests the 3-(thien-3-yl)-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxide (13d) showed selective anticonvulsant activity.
Assuntos
Óxidos N-Cíclicos/síntese química , Receptores de GABA-A/metabolismo , Triazinas/síntese química , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Bovinos , Córtex Cerebral/metabolismo , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Óxidos N-Cíclicos/farmacologia , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Relaxantes Musculares Centrais/síntese química , Relaxantes Musculares Centrais/química , Relaxantes Musculares Centrais/metabolismo , Relaxantes Musculares Centrais/farmacologia , Ensaio Radioligante , Triazinas/química , Triazinas/metabolismo , Triazinas/farmacologiaRESUMO
The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.
Assuntos
Inibidores da Captação de Neurotransmissores/farmacologia , Ácidos Nipecóticos/farmacologia , Nociceptores/efeitos dos fármacos , Receptores de GABA-B/metabolismo , Abdome/fisiopatologia , Animais , Baclofeno/farmacologia , Constrição Patológica/induzido quimicamente , Constrição Patológica/prevenção & controle , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Espaço Extracelular/metabolismo , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Masculino , Camundongos , Microdiálise , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Compostos Organofosforados/farmacologia , Dor/prevenção & controle , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Tálamo/fisiopatologia , Tiagabina , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
To characterize the mechanism of the analgesic action of H1 antihistaminics the effects of a new, highly selective agonist, 2-(3-trifluoromethylphenyl)histamine dihydrogenmaleate (FMPH), and of the better known H1 agonist, 2-thiazolylethylamine (2-TEA), were studied on pain threshold by means of three different kinds of tests for nociception (mouse hot plate and abdominal constriction, and rat paw pressure tests). Low doses of both substances (2.65 and 6.5 microg/animal i.c.v. for FMPH in the hot plate and paw pressure tests, and 0.3 microg/rat i.c.v. for 2-TEA in the paw pressure test) were slightly but significantly hypernociceptive. The selective H1 receptor antagonist, pyrilamine maleate (10-30 mg/kg s.c.), induced a dose-dependent antinociception in all three tests, and both FMPH and 2-TEA prevented its effect, but not that of morphine, thus indicating action on H1 receptors. The same low doses of FMPH were also able to enhance animals' spontaneous motility and curiosity. High doses of FMPH (13.23-132.3 microg/mouse i.c.v.) raised the pain threshold, but due to the severe motor impairment evidenced by the rota rod test, this cannot be considered as real antinociception. An increase in the pain threshold lacking any motor impairment was observed for tenfold higher doses of 2-TEA (3 and 10 microg/mouse i.c.v.). This may be due to action on H2 receptors, with the reported relative potency of 2-TEA for H1 and H2 receptors being about 12:1. It is therefore suggested that H1 receptor activation increases sensitivity to noxious stimuli.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Histamina/análogos & derivados , Nociceptores/metabolismo , Receptores Histamínicos H1/metabolismo , Tiazóis/farmacologia , Animais , Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Camundongos , Nociceptores/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Pirilamina/farmacologia , Ratos , Ratos Wistar , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H2/metabolismoRESUMO
1. Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. 2. Imipramine (10 and 30 mg kg(-1), i.p.) and amitriptyline (5 and 15 mg kg(-1), i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)-alpha-methylhistamine, at a dose (10 mg kg(-1), i.p.) which did not modify the cumulative time of immobility. 3. The histamine H3 receptor antagonist, thioperamide (2-20 mg kg(-1), s.c.), showed an antidepressant-like effect, with a maximum at the dose of 5 mg kg(-1), which was completely prevented by (R)-alpha-methylhistamine. 4. The histamine-N-methyltransferase inhibitor, metoprine (2-20 mg kg(-1), s.c.), was effective with an ED50 of 4.02 (2.71-5.96) mg kg(-1); its effect was prevented by (R)-alpha-methylhistamine. 5. The histamine precursor, L-histidine (100-1000 mg kg(-1), i.p.), dose-dependently decreased the time of immobility [ED30 587 (499-712) mg kg(-1)]. The effect of 500 mg kg(-1) L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-alpha-fluoromethylhistidine (50 mg kg(-1), i.p.), administered 15 h before. 6. The highly selective histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl)histamine (0.3-6.5 microg per mouse, i.c.v.), and the better known H1 agonist, 2-thiazolylethylamine (0.1-1 microg per mouse, i.c.v.), were both dose-dependently effective in decreasing the time of immobility [ED50 3.6 (1.53-8.48) and 1.34 (0.084-21.5) microg per mouse, respectively]. 7. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test. 8. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like effect, via activation of H1 receptors.
Assuntos
Antidepressivos/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/análogos & derivados , Histamina/fisiologia , Estresse Fisiológico/fisiopatologia , Tiazóis/farmacologia , Animais , Histamina/farmacologia , Masculino , Camundongos , Receptores Histamínicos H1/efeitos dos fármacos , Padrões de ReferênciaRESUMO
Immunocytochemical analysis of breast carcinoma specimens for alpha 6 beta 4 integrin expression and other different pathobiological markers revealed beta 4 integrin subunit expression in 36 of 80 cases analyzed and a significant association only with alpha 6 integrin subunit expression (P < 0.01) and laminin production (P = 0.01) by tumor cells. Survival analysis indicated that beta 4 and alpha 6 expression are associated with poor prognosis (P = 0.02), whereas laminin production showed only borderline association (P = 0.06). However, analysis of disease outcome in relation to expression of both alpha 6 beta 4 and laminin indicated best outcomes for patients with tumors producing laminin but not expressing alpha 6 beta 4 integrin, whereas worst outcomes were observed for alpha 6 beta 4- and laminin-positive tumors, indicating that alpha 6 beta 4 expression was associated with prognosis, mainly in the laminin-producing tumor subset. These data indicate that the prognostic value of alpha 6 beta 4 integrin expression is affected by laminin production from tumor cells and suggest that interaction between these two molecules mediates distinct signals that are important for tumor progression.
Assuntos
Antígenos de Superfície/biossíntese , Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/metabolismo , Integrinas/biossíntese , Laminina/biossíntese , Neoplasias da Mama/patologia , Humanos , Imuno-Histoquímica , Integrina alfa6beta4 , Estadiamento de Neoplasias , PrognósticoRESUMO
The antinociceptive effect of (+/-)-3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate [corrected] (SM-21) (10-40 mg kg(-1) s.c., 10-30 mg kg(-1) i.p., 20-60 mg kg(-1) p.o., 3-20 mg kg(-1) i.v. and 5-20 microg per mouse i.c.v.) was examined in rodents and guinea pigs by using the hot-plate, abdominal constriction, tail-flick and paw-pressure tests. The antinociception produced by (+/-)-SM-21 was prevented by atropine, pirenzepine and hemicholinium-3 but not by quinpirole, R-(alpha)-methylhistamine, [1-[2(methylsufonyl)amino]ethyl]-4-piperidinyl]methyl-5-floro++ +-2-methoxy-1H-indole-3-carboxylate hydrochloride, N6-cyclopentyladenosine, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide, naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid or reserpine. On the basis of the above data, it can be postulated that (+/-)-SM-21 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. Affinity profiles of (+/-)-SM-21 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4) have shown a selectivity ratio M2/M1 of 4.6 that, although very low, might be responsible for the antinociception induced by (+/-)-SM-21 through an increase in ACh extracellular levels. In the antinociceptive dose range, (+/-)-SM-21 did not impair mouse performance evaluated by the rota-rod and hole-board tests.
Assuntos
Analgésicos/farmacologia , Butiratos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Receptores Pré-Sinápticos/efeitos dos fármacos , Tropanos/farmacologia , Animais , Atropina/farmacologia , Cobaias , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Coelhos , Ratos , EstereoisomerismoRESUMO
We have previously reported that the histaminergic system is involved in the control of pain perception, and that substances able to enhance histamine brain levels, such as the histamine-N-methyltransferase inhibitor, metoprine, induce antinociception. In the present study, in order to corroborate the idea of inducing antinociception by inhibiting histamine catabolism, the effects of a noncompetitive histamine-N-methyltransferase inhibitor. SKF 91488, were studied in rodents by means of tests inducing three different kinds of noxious stimuli: thermal (mouse hot plate), chemical (mouse abdominal constrictions) and mechanical (rat paw pressure). The ability to react to noxious stimuli was assessed by the rota-rod test. In addition, a competitive inhibitor of the histamine catabolism enzyme, BW 301 U, was studied in the hot plate test. SKF 91488 (30, 50 and 100 micrograms per animal i.c.v.) raised dose-dependently the pain threshold in all three tests. To verify whether SKF 91488-induced antinociception is due to inhibition of histamine-N-methyltransferase, (R)-alpha-methylhistamine, described to block histamine release and synthesis by stimulating the histamine H3-autoreceptor and activating the negative feed-back mechanism, was used. When administered at doses which do not alter the pain threshold per se, 0.5 microgram per rat i.c.v. or 10 mg kg-1 i.p. in mice, (R)-alpha-methylhistamine was able to antagonize significantly the antinociceptive effect induced by 30 micrograms per animal i.c.v. of SKF 91488. BW 301 U (30 and 100 mg kg-1 i.p.) showed a dose-dependent, long-lasting antinociception, which was also antagonized by pretreatment with (R)-alpha-methylhistamine. The present data show that the antinociceptive effect previously described for metoprine is not restricted to this molecule, but is also shared by other histamine-N-methyl-transferase inhibitors. This generalization provides further evidence to the importance of the histaminergic system in pain control mechanisms.