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1.
Hastings Cent Rep ; 53(2): 36-43, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-37092649

RESUMO

Over the past several decades in which access to abortion has become increasingly restricted, parents' autonomy in medical decision-making in the realms of fetal care and neonatal intensive care has expanded. Today, parents can decide against invasive medical interventions at gestational ages where abortions are forbidden, even in cases where neonates are expected to be seriously ill. Although a declared state interest in protecting the lives of fetuses and newborns contributes to justifications for restricting women's autonomy with regards to abortion, it does not fully explain this discrepancy. We believe that social portrayals of women as complying with or shirking their reproductive function play a major role in explaining it. The growing divide between a woman's rights as a reproductive being and as a parent suggest that abortion restriction is rooted in a historical societal desire for women to serve as reproducers and in the corresponding fear of them abandoning this allotted role in pursuit of social equality. The Dobbs v. Jackson (2022) decision is not based in a view of abortion as a medical act occurring between a doctor and patient, as Roe v. Wade (1973) did, but decision-making about fetal therapy or NICU care is still viewed as occurring between a doctor and patient or surrogate because in this act a woman is seen as fulfilling her role as mother.


Assuntos
Aborto Induzido , Terapias Fetais , Recém-Nascido , Humanos , Gravidez , Feminino , Estados Unidos , Unidades de Terapia Intensiva Neonatal , Motivação , Aborto Legal
2.
Leukemia ; 28(10): 1960-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24577530

RESUMO

Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Benzofuranos/uso terapêutico , Leucemia/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Leucócitos Mononucleares/citologia , Camundongos , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/citologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Células-Tronco/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Thromb Res ; 104(4): 297-9, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11728532

RESUMO

BACKGROUND: Chronic drug abuse is an established cause of acute coronary events and sudden death. The association between use of narcotics and platelet abnormalities is well described. However, it is still not clear, how aspirin affects expression of major platelet receptors in chronic drug users with coronary artery disease, especially those recovering in the methadone clinic maintenance program. We sought to compare how a single pill of non-enteric coated aspirin (325-mg) affects human platelets in patients with coronary artery disease dependent on methadone use. METHODS: Data from 30 subjects were analyzed, eight of them were the chronic drug addicts, and participated in a methadone recovery program. Platelets were assessed twice at baseline (pre-aspirin), and after 3-24 hours (post-aspirin). The expression of platelet receptors was determined by using the following monoclonal antibodies: CD31 (PECAM-1), CD41 (GPIIb), CD42b (GPIb), CD51/CD61 (vitronectin receptor), CD62p (P-selectin), CD63 (LIMP or LAMP-3), CD107a (LAMP-1), CD151 (PETA-3), and PAC-1 for fibrinogen-platelet binding determination (PharMingen, San Diego, CA). Platelet-leukocyte interactions were assessed by using dual antibodies for a pan-platelet marker (CD151), together with CD14, a monocyte/macrophage marker. RESULTS: In a drug free group, digestion of a single tablet of aspirin resulted in a significantly (p<0.05) diminished expression of PECAM-1, GP IIb, fibrinogen binding with PAC-1 antibody, GP Ib, P-selectin, and CD151. In contrast, patients receiving methadone exhibited opposite trends, resultant in a paradoxical activation of major platelet receptors after digestion of aspirin. These differences reached statistical significance (p<0.05) for PECAM-1, GPIIb, and P-selectin expression. CONCLUSION: There are some fundamental differences in the responsiveness to aspirin in chronic methadone users when compared with drug-free patients. Suspecting narcotics abuse may be critical in patients with limited aspirin efficacy, or those who developed an aspirin resistance. Unexpected platelet activation may indeed represent a missing link between use of narcotics and enhanced incidence of vascular death in this high-risk population.


Assuntos
Aspirina/efeitos adversos , Metadona/efeitos adversos , Glicoproteínas da Membrana de Plaquetas/efeitos dos fármacos , Adulto , Aspirina/administração & dosagem , Doença da Artéria Coronariana/sangue , Interações Medicamentosas , Feminino , Humanos , Masculino , Metadona/administração & dosagem , Pessoa de Meia-Idade , Selectina-P/efeitos dos fármacos , Selectina-P/metabolismo , Adesividade Plaquetária/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Transtornos Relacionados ao Uso de Substâncias/sangue
5.
Swiss Med Wkly ; 131(33-34): 487-9, 2001 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-11683077

RESUMO

Numerous reports document the widespread use of cocaine in most parts of the world, which confers an increased risk of vascular morbidity and mortality. The mechanisms responsible for this association are multifactorial, but platelet activation might play a substantial role linking these events. Contradictory data exist regarding the cellular mechanisms of cocaine's effects on thrombocytes. In terms of therapeutic interventions, a possible activation of platelets would conceptually require more aggressive anti-platelet therapy with aspirin, clopidogrel or other compounds, however, no data exist to date to support this approach. Further studies elucidating these issues are warranted. This review summarizes the latest and often confusing data on the interaction between cocaine and platelets in certain in vitro, animal and clinical scenarios.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/complicações , Cocaína/efeitos adversos , Infarto do Miocárdio/etiologia , Ativação Plaquetária/efeitos dos fármacos , Animais , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Infarto do Miocárdio/induzido quimicamente
7.
Cardiology ; 95(2): 55-60, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11423707

RESUMO

Fibrinolytic therapy is the established treatment for the management of patients with ST elevation acute myocardial infarction (AMI). Present fibrinolytic regimens have a number of shortcomings, including the failure to produce early and sustained reperfusion, as well as failure to prevent reocclusion in at least some patients. Platelets play an important role in coronary thrombosis responsible for AMI. The effect of coronary fibrinolysis on platelets has been extensively debated in the literature with evidence of both platelet activation and inhibition. Among fibrinolytic agents, tissue plasminogen activator (t-PA) is considered to be the mainstay in the treatment of coronary artery disease. The native t-PA molecule has been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. The result is a group of mutant t-PA variants considered third-generation plasminogen activators. TNK-t-PA is one bioengineered variant of t-PA. Another third-generation plasminogen activator is reteplase (r-PA). Like TNK-t-PA, it is a variant of t-PA that has been developed to establish a more rapid, complete, and stable coronary artery patency, thus promising reduced mortality. Both r-PA and TNK-t-PA are effective when given as bolus therapy. This feature may facilitate more rapid treatment as well as decrease overall costs of treatment. New fibrinolytic regimens include potent antiplatelet agents that may improve sustained reperfusion. This review summarizes the latest and often confusing data on the interaction between fibrinolytic therapy and platelets in certain in vitro, animal and clinical scenarios.


Assuntos
Plaquetas/efeitos dos fármacos , Fibrinolíticos/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Ativadores de Plasminogênio/efeitos adversos , Terapia Trombolítica/efeitos adversos , Animais , Plaquetas/fisiologia , Fibrinolíticos/uso terapêutico , Humanos , Ativadores de Plasminogênio/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estreptoquinase/efeitos adversos , Estreptoquinase/uso terapêutico , Tenecteplase , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico
8.
J Med Chem ; 18(11): 1088-94, 1975 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-126324

RESUMO

Based on the known curariform action of tris(bipyridyl)iron(II) sulfate and other complex ions, two series of bifunctional ligands designed to hold transition metal ions at approximately the same distance apart as the interquaternary ammonium distance in the potent neuromuscular block agents were synthesized. In the first series two 1,10-phenanthrolines (R1) were joined at the 2 position to form four compounds: R1CO-c-N(CH2CH2)2N-COR1, R1CONH-1,2-C6H10-NHCOR1, R1CONH-1,2-C6H4-NHCOR1, and R1CON(CH3)(CH2)2N(CH3)COR1. In the second series two terpyridines (R1) were joined by different chains to give R2(CH2)2CH=CH(CH2)2R2, R2CH2C(CH3)(OH)(CH2)2C(CH23)(OH)CH2R2, R2CH2C(CH3)(OH)C(CH3)(OH)CH2R2, and R2CH2(OH)-1,4-C6H10-(OH)CH2R2. Three other ligands in which the terpyridines were joined by 5-, 60, and 7-methylene groups were also made. The ligands were converted to nickel(II) complexes and the coordination of each nickel ion was completed by adding terpyridine. These were assayed by the intravenous mouse LD50 method. The most potent ligand, the di-hydroxy compound R2CH2(OH)-1,4-C6H10-(OH)CH2R2 was then converted to the bis(pyridinebipyridine)diosmium-(II) coordinated complex and assayed by the iv mouse LD50 method and by the ED50 isolated guinea-pig diaphragm method. By the iv mouse LD50 method, it was about twice as potent as d-tubocurarine and by the isolated diaphragm method, it was 16 times more potent. The compound has been called dihydroxyosmarine tetrachloride or DHO for short. The term "transarine" ions is proposed for transition metal coordination complexes having curariform action. The position of the transarine ions is discussed in the classification of cholinergic ligands, in structure-action relationships, and in relation to some current ideas on receptor mechanisms.


Assuntos
Fármacos Neuromusculares não Despolarizantes/síntese química , Osmio , Fenantrolinas/síntese química , Piridinas/síntese química , Animais , Diafragma/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Dose Letal Mediana , Ligantes , Camundongos , Contração Muscular/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Fármacos Neuromusculares não Despolarizantes/toxicidade , Osmio/farmacologia , Osmio/toxicidade , Fenantrolinas/farmacologia , Fenantrolinas/toxicidade , Piridinas/farmacologia , Piridinas/toxicidade
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