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1.
Cardiovasc Pathol ; 46: 107194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31982687

RESUMO

BACKGROUND: Celecoxib, a selective cyclooxygenase-2 inhibitor, was recently associated with increased incidence of aortic stenosis and found to produce a valvular calcification risk in vitro. Several cyclooxygenase-2 independent celecoxib derivatives have been developed and identified as possible therapies for inflammatory diseases due to their cadherin-11 inhibitory functions. Potential cardiovascular toxicities associated with these cyclooxygenase-2 independent celecoxib derivatives have not yet been investigated. Furthermore, the mechanism by which celecoxib produces valvular toxicity is not known. METHODS AND RESULTS: Celecoxib treatment produces a 2.8-fold increase in calcification in ex vivo porcine aortic valve leaflets and a more than 2-fold increase in calcification in porcine aortic valve interstitial cells cultured in osteogenic media. Its cyclooxygenase-2 independent derivative, 2,5-dimethylcelecoxib, produces a similar 2.5-fold increase in calcification in ex vivo leaflets and a 13-fold increase in porcine aortic valve interstitial cells cultured in osteogenic media. We elucidate that this offtarget effect depends on the presence of either of the two media components: dexamethasone, a synthetic glucocorticoid used for osteogenic induction, or cortisol, a natural glucocorticoid present at basal levels in the fetal bovine serum. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. By adding glucocorticoids or hydrocortisone to a serum substitute lacking endogenous glucocorticoids, we show that dimethylcelecoxib conditionally induces a 3.5-fold increase in aortic valve calcification and osteogenic expression. Treatment with the Mitogen-activated protein kinase kinase inhibitor, U0126, rescues the offtarget effect, suggesting that celecoxib and dimethylcelecoxib conditionally augment Mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase activity in the presence of glucocorticoids. CONCLUSION: Here we identify glucocorticoids as a possible source of the increased valvular calcification risk associated with celecoxib and its cyclooxygenase-2 independent derivatives. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. Furthermore, the offtarget effects are not due to the drug's intrinsic properties as dual cyclooxygenase-2 and cadherin-11 inhibitors. These findings inform future design and development of celecoxib derivatives for potential clinical therapy.


Assuntos
Valva Aórtica/efeitos dos fármacos , Calcinose/induzido quimicamente , Celecoxib/toxicidade , Inibidores de Ciclo-Oxigenase 2/toxicidade , Dexametasona/toxicidade , Glucocorticoides/toxicidade , Doenças das Valvas Cardíacas/induzido quimicamente , Hidrocortisona/toxicidade , Osteogênese/efeitos dos fármacos , Pirazóis/toxicidade , Sulfonamidas/toxicidade , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Caderinas/genética , Caderinas/metabolismo , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Celecoxib/análogos & derivados , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Sus scrofa , Técnicas de Cultura de Tecidos
2.
Autoimmunity ; 52(2): 78-87, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31062619

RESUMO

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune mediated diseases triggered by group A streptococcal (GAS) infections. Molecular mimicry between GAS M-proteins and host tissue proteins has been proposed as the mechanism that initiates autoreactive immune responses in ARF/RHD. However, the individual role of antibodies and T-cells specific for GAS M-proteins in the pathogenesis of autoimmune carditis remains under-explored. The current study investigated the role of antibodies and T-cells in the development of carditis in the Lewis rat autoimmune valvultis (RAV) model by transferring serum and/or splenic T-cells from rats previously injected with GAS recombinant M5 protein. Here we report that serum antibodies alone and serum plus in vitro expanded rM5-specific T-cells from hyperimmune rats were capable of transferring carditis to naïve syngeneic animals. Moreover, the rats that received combined serum and T-cells developed more severe carditis. Recipient rats developed mitral valvulitis and myocarditis and showed prolongation of P-R intervals in electrocardiography. GAS M5 protein-specific IgG reactivity and T-cell recall response were also demonstrated in recipient rats indicating long-term persistence of antibodies and T-cells following transfer. The results suggest that both anti-GAS M5 antibodies and T-cells have differential propensity to induce autoimmune mediated carditis in syngeneic rats following transfer. The results highlight that antibodies and effector T-cells generated by GAS M protein injection can also independently home into cardiac tissue to cross-react with tissue proteins causing autoimmune mediated immunopathology.


Assuntos
Antígenos de Bactérias/toxicidade , Doenças Autoimunes , Proteínas da Membrana Bacteriana Externa/toxicidade , Proteínas de Transporte/toxicidade , Doenças das Valvas Cardíacas , Cardiopatia Reumática , Streptococcus pyogenes , Linfócitos T , Animais , Antígenos de Bactérias/imunologia , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Feminino , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/imunologia , Doenças das Valvas Cardíacas/patologia , Ratos , Ratos Endogâmicos Lew , Cardiopatia Reumática/induzido quimicamente , Cardiopatia Reumática/imunologia , Cardiopatia Reumática/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
3.
Sci Rep ; 8(1): 17835, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546028

RESUMO

The purpose of this study was to test the hypothesis that an experimental high fat (HF) animal with metabolic syndrome results in structural degeneration of the aortic valve. Domestic pigs were divided (n = 12) and administered either a normal or HF diet. After 16-weeks, the HF diet group had increased weight (p ≤ 0.05), total cholesterol (p ≤ 0.05), and systolic and diastolic pressure (p ≤ 0.05). The aortic valve extracellular matrix showed loss of elastin fibers and increased collagen deposition in the HF diet group. Collagen was quantified with ELISA, which showed an increased concentration of collagen types 1 and 3 (p ≤ 0.05). In the HF diet group, the initial stages of microcalcification were observed. Uniaxial mechanical testing of aortic cusps revealed that the HF diet group expressed a decrease in ultimate tensile strength and elastic modulus compared to the control diet group (p ≤ 0.05). Western blot and immunohistochemistry indicated the presence of proteins: lipoprotein-associated phospholipase A2, osteopontin, and osteocalcin with an increased expression in the HF diet group. The current study demonstrates that experimental metabolic syndrome induced by a 16-week HF diet was associated with a statistically significant alteration to the physical architecture of the aortic valve.


Assuntos
Valva Aórtica , Gorduras na Dieta/efeitos adversos , Doenças das Valvas Cardíacas , Síndrome Metabólica , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Osteocalcina/metabolismo , Osteopontina/metabolismo , Suínos
5.
Reumatol. clín. (Barc.) ; 14(5): 269-277, sept.-oct. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-175988

RESUMO

Objetivos: Estudiar las características clínicas y desenlaces de los pacientes con lupus eritematoso sistémico (LES) intervenidos de cirugía cardiaca. Métodos: Se realizó un estudio retrospectivo de 30 pacientes con LES y cirugía cardiaca en un solo centro. Se registraron comorbilidades, características demográficas, clínicas, serológicas, riesgo cardiovascular, tratamiento, tipo de cirugía, complicaciones postoperatorias, mortalidad e histología. Resultados: La duración de LES al momento de la cirugía fue de 2 años. El procedimiento más frecuente fue recambio valvular (53%), seguido de ventana pericárdica (37%). Al menos una complicación postoperatoria se presentó en el 63% (principalmente infecciones). Un pinzamiento aórtico≥76 min se asoció con al menos una complicación (OR 6,4; IC 95% 1,1-35,4, p=0,03). La mortalidad temprana ocurrió en 5 pacientes (17%) y tardía en 3 (10%); siendo las causas principales sepsis e insuficiencia cardiaca. La actividad de la enfermedad se asoció a la realización de ventana pericárdica (OR 12,6; IC 95% 1,9-79; p=0,007), presencia de linfopenia≤1.200 (OR 10,1; IC 95% 1,05-97; p=0,04), edad≤30 años (OR 7,7; IC 95% 1,2-46,3; p=0,02) y NYHA clase III (OR 7,0; IC 95% 1,1-42, p=0,03). El desarrollo de infección postoperatoria se asoció con estancia hospitalaria≥2 semanas (OR 54,9; IC 95% 5,0-602,1; p=0,001), estancia en UCI≥10 días (OR 20; IC 95% 1,6-171,7, p=0,01), duración de ventilación mecánica ≥ 5 días (OR 16,9, IC 95% 1,5-171,7, p = 0,01) y PSAP≥50mmHg (OR 7,8; IC 95% 1,4-41,2; p=0,01). Conclusiones: La cirugía cardiaca en LES se asocia a alta morbimortalidad


Objectives: To study the clinical characteristics and outcomes in systemic lupus erythematosus (SLE) patients who underwent cardiac surgery. Methods: Retrospective analysis of 30 SLE patients who underwent cardiac surgery at a single center. Demographics, comorbidities, clinical and serologic characteristics, cardiovascular risk scores and treatment were recorded. Type of surgery, postoperative complications, mortality and histology were analyzed. Results: Disease duration at surgery was 2 years. Valve replacement was the procedure most frequently performed (53%), followed by pericardial window (37%). At least one postoperative complication developed in 63% (mainly infections). An aortic cross-clamp time≥76minutes was associated with at least one postoperative complication (OR 6.4, 95% CI 1.1-35.4, p=.03). Early death occurred in 5 patients (17%) and late in 3 (10%); main causes were sepsis and heart failure. Disease activity was associated with pericardial window (OR 12.6, 95% CI 1.9-79, p=.007); lymphopenia≤1.200 (OR 10.1, 95% CI 1.05-97, p=.04); age≤30 years (OR 7.7, 95% CI 1.2-46.3, p=.02); and New York Heart Association class III (OR 7.0, 95% CI 1.1-42, p=.03). Postoperative infection was associated with length of hospital stay≥2 weeks (OR 54.9, 95% CI 5.0-602.1, p=.001); intensive care unit stay≥10 days (OR 20, 95% CI 1.6-171.7, p=.01); duration of mechanical ventilation≥5 days (OR 16.9, 95% CI 1.5-171.7, p=.01); and pulmonary artery systolic pressure≥50mmHg (OR 7.8, 95% CI 1.4-41.2, p=.01). Conclusions: Cardiac surgery in SLE confers high morbidity and mortality. SLE-specific preoperative risk scores should be designed to identify prognostic factors


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Lúpus Eritematoso Sistêmico/complicações , Cardiopatias/cirurgia , Estudos Retrospectivos , Cardiopatias/complicações , Comorbidade , Fatores de Risco , Glucocorticoides/efeitos adversos , Anticorpos Anticardiolipina/análise , Pericardite/epidemiologia , Doenças das Valvas Cardíacas/induzido quimicamente , Avaliação de Resultados da Assistência ao Paciente
6.
Toxicol Appl Pharmacol ; 355: 147-155, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30008375

RESUMO

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.


Assuntos
Fármacos Antiobesidade/toxicidade , Anticorpos Monoclonais/toxicidade , Doenças das Valvas Cardíacas/induzido quimicamente , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/efeitos dos fármacos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/efeitos dos fármacos , Animais , Fármacos Antiobesidade/farmacocinética , Anticorpos Monoclonais/farmacocinética , Osso e Ossos/patologia , Ingestão de Alimentos/efeitos dos fármacos , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Valvas Cardíacas/metabolismo , Valvas Cardíacas/patologia , Masculino , Osteogênese/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Perda de Peso/efeitos dos fármacos
7.
J Neural Transm (Vienna) ; 125(6): 953-963, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29484495

RESUMO

Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non-ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for ≤ 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine-substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally-related to rotigotine.


Assuntos
Antiparkinsonianos/uso terapêutico , Agonistas de Dopamina/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Idoso , Antiparkinsonianos/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Tetra-Hidronaftalenos/efeitos adversos , Tiofenos/efeitos adversos , Adesivo Transdérmico , Resultado do Tratamento
8.
J Biol Chem ; 293(10): 3780-3792, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29358327

RESUMO

The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participates in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification. Immunostaining, quantitative PCR, and Western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNA-mediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification, and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.


Assuntos
Valva Aórtica/metabolismo , Calcinose/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Doenças das Valvas Cardíacas/metabolismo , Fatores de Transcrição da Família Snail/agonistas , Proteína Supressora de Tumor p53/metabolismo , Animais , Anticoagulantes/efeitos adversos , Antifibrinolíticos/efeitos adversos , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Calcinose/induzido quimicamente , Calcinose/patologia , Células Cultivadas , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/efeitos dos fármacos , Interferência de RNA , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/patologia , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Sus scrofa , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Vitamina K 1/efeitos adversos , Varfarina/efeitos adversos
9.
Cardiovasc Eng Technol ; 9(2): 168-180, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28247311

RESUMO

While the valvulopathic effects of serotonin (5HT) and angiotensin-II (Ang-II) individually are known, it was not clear how 5HT and Ang-II might interact, specifically in the context of the mechanobiological responses due to altered valve mechanics potentiated by these molecules. In this context, the hypothesis of this study was that increased serotonin levels would result in accelerated progression toward disease in the presence of angiotensin-II-induced hypertension. C57/BL6 J mice were divided into four groups and subcutaneously implanted with osmotic pumps containing: PBS (control), 5HT (2.5 ng/kg/min), Ang-II (400 ng/kg/min), and 5HT + Ang-II (combination). Blood pressure was monitored using the tail cuff method. Echocardiography was performed on the mice before surgery and every week thereafter to assess ejection fraction. After three weeks, the mice were sacrificed and their hearts excised, embedded and sectioned for analysis of the aortic valves via histology and immunohistochemistry. In separate experiments, porcine valve interstitial cells (VICs) were directly stimulated with 5HT (10-7 M), Ang-II (100 nM) or both and assayed for cellular contractility, cytoskeletal organization and collagen remodeling. After three weeks, average systolic blood pressure was significantly increased in the 5HT, Ang-II and combination groups compared to control. Echocardiographic analysis demonstrated significantly reduced ejection fraction in Ang-II and the combination groups. H&E staining demonstrated thicker leaflets in the combination groups, suggesting a more aggressive remodeling process. Picrosirius red staining and image analysis suggested that the Ang-II and combination groups had the largest proportion of thicker collagen fibers. VIC orientation, cellular contractility and collagen gene expression was highest for the 5HT + Ang-II combination treatment compared to all other groups. Overall, our results suggest that 5HT and Ang-II interact to result in significantly detrimental alteration of function and remodeling in the valve.


Assuntos
Angiotensina II , Valva Aórtica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doenças das Valvas Cardíacas/induzido quimicamente , Hipertensão/induzido quimicamente , Serotonina/toxicidade , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Modelos Animais de Doenças , Feminino , Colágenos Fibrilares/metabolismo , Fibrose , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/fisiopatologia , Hipertensão/fisiopatologia , Mecanotransdução Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Volume Sistólico/efeitos dos fármacos , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacos
10.
Vnitr Lek ; 63(9): 561-565, 2017.
Artigo em Tcheco | MEDLINE | ID: mdl-29120651

RESUMO

Adverse effect of dopamine agonists on the heart valves aroused much attention some time ago. Gradually, as data accumulated, the approach to the problem was rationalised and further examinations were only recommended in indicated cases. The paper reviews the current knowledge about the treatment of hyperprolactinemia with dopamine agonists and the risk of valvular disease.Key words: dopamine agonists - ergolines/adverse effects - heart valve diseases - hyperprolactinemia - pituitary neoplasms - prolactinoma.


Assuntos
Agonistas de Dopamina/uso terapêutico , Doenças das Valvas Cardíacas/induzido quimicamente , Hiperprolactinemia/tratamento farmacológico , Ergolinas/uso terapêutico , Humanos
12.
Toxicol Pathol ; 45(3): 381-388, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28421966

RESUMO

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on Ki values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC50 or EC50/human fCmax values for determining whether known 5-HT2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.


Assuntos
Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Doenças das Valvas Cardíacas/induzido quimicamente , Medição de Risco , Agonistas do Receptor 5-HT2 de Serotonina/toxicidade , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Regulamentação Governamental , Doenças das Valvas Cardíacas/metabolismo , Humanos , Técnicas In Vitro , Ligação Proteica , Receptores 5-HT2 de Serotonina/metabolismo , Medição de Risco/legislação & jurisprudência , Medição de Risco/métodos , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética
13.
Medicine (Baltimore) ; 96(2): e4985, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28079786

RESUMO

RATIONALE: Drug-induced valvular heart disease (DI-VHD) remains an under-recognized entity. PATIENT CONCERNS: This report describes a heart valve replacement which was complicated by intractable systemic pulmonary arterial hypertension in a 61-year-old female with severe restrictive mitral and aortic disease. The diagnosis of valvular disease was preceded by a history of unexplained respiratory distress. The patient had been exposed to benfluorex for 6.5 years. DIAGNOSES: The diagnostic procedure documented specific drug-induced valvular fibrosis. INTERVENTIONS: Surgical mitral and aortic valve replacement was performed. OUTCOMES: Heart valve replacement was postoperatively complicated by unanticipated disproportionate pulmonary hypertension. This issue was fatal despite intensive care including prolonged extracorporeal life support. LESSONS: Benfluorex is a fenfluramine derivative which has been marketed between 1976 and 2009. Although norfenfluramine is the common active and toxic metabolite of all fenfluramine derivatives, the valvular and pulmonary arterial toxicity of benfluorex was much less known than that of fenfluramine and dexfenfluramine. The vast majority of benfluorex-induced valvular heart disease remains misdiagnosed as hypothetical rheumatic fever due to similarities between both etiologies. Better recognition of DI-VHD is likely to improve patient outcome.


Assuntos
Depressores do Apetite/efeitos adversos , Fenfluramina/análogos & derivados , Doenças das Valvas Cardíacas/induzido quimicamente , Hipertensão Pulmonar/etiologia , Complicações Pós-Operatórias/etiologia , Evolução Fatal , Feminino , Fenfluramina/efeitos adversos , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca , Humanos , Pessoa de Meia-Idade
14.
J Heart Valve Dis ; 26(4): 467-471, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-29302947

RESUMO

BACKGROUND AND AIM OF THE STUDY: Fenfluraminephentermine (FenPhen) has been implicated in accelerated valvular heart disease, characterized by valvular regurgitation and thickening, and resembling the histopathologic lesions found in carcinoid. The study aim was to determine whether cellular proliferation is present in FenPhen-exposed valves, by utilizing an in-vitro model to test whether FenPhen has a direct mitogenic effect on cardiac valvular cells, as compared to serotonin. METHODS: Ex-vivo valves were tested for proliferation in surgically removed FenPhen-exposed valves (n = 10) and compared to proliferation levels in normal human cardiac valves removed at autopsy (n = 10). Immunostaining for a DNA polymerase, proliferating cell nuclear antigen (PCNA), was performed and quantified using digital imaging analysis. In-vitro assays were performed for direct proliferative effects of serotonin and FenPhen (10-6, 10-7 and 10-8 M) on porcine aortic valve subendothelial cells, using a [3H]-thymidine incorporation assay. RESULTS: Ex-vivo PCNA levels in human FenPhenexposed valves were elevated compared to controls (22.8 ± 4.54 versus 1.26 ± 0.47; p <0.001). In vivo, serotonin and FenPhen markedly increased (10-fold) cell proliferation (as measured by [3H]-thymidine incorporation) in subendothelial cells in vitro (p <0.001). This proliferative response was demonstrated by PCNA staining in carcinoid heart valves and FenPhen-exposed valves. Mechanistically, plateletderived growth factor increased cell proliferation in a dose-related manner (p <0.001), the response being inhibited by a MAP kinase inhibitor (determined by monitoring p42/44 levels). CONCLUSIONS: In vitro, FenPhen acts as a powerful mitogen on subendothelial myofibroblast valve cells. Ex vivo, cellular proliferation was significantly elevated in human FenPhen-exposed cells.


Assuntos
Fármacos Antiobesidade/toxicidade , Valva Aórtica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fenfluramina/toxicidade , Doenças das Valvas Cardíacas/induzido quimicamente , Miofibroblastos/efeitos dos fármacos , Fentermina/toxicidade , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Cardiotoxicidade , Estudos de Casos e Controles , Células Cultivadas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fenfluramina/química , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Humanos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fentermina/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Serotonina/toxicidade , Transdução de Sinais/efeitos dos fármacos
15.
J Agric Food Chem ; 64(47): 9078-9088, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27792329

RESUMO

As a neonicotinoid pesticide, imidacloprid is widely used to control sucking insects on agricultural planting and fleas on domestic animals. However, the extent to which imidacloprid exposure has an influence on cardiogensis in early embryogenesis is still poorly understood. In vertebrates, the heart is the first organ to be formed. In this study, to address whether imidacloprid exposure affects early heart development, the early chick embryo has been used as an experimental model because of its accessibility at its early developmental stage. The results demonstrate that exposure of the early chick embryo to imidacloprid caused malformation of heart tube. Furthermore, the data reveal that down-regulation of GATA4, NKX2.5, and BMP4 and up-regulation of Wnt3a led to aberrant cardiomyocyte differentiation. In addition, imidacloprid exposure interfered with basement membrane breakdown, E-cadherin/laminin expression, and mesoderm formation during the epithelial-mesenchymal transition (EMT) in gastrula chick embryos. Finally, the DiI-labeled cell migration trajectory indicated that imidacloprid restricted the cell migration of cardiac progenitors to primary heart field in gastrula chick embryos. A similar observation was also obtained from the cell migration assay of scratch wounds in vitro. Additionally, imidacloprid exposure negatively affected the cytoskeleton structure and expression of corresponding adhesion molecules. Taken together, these results reveal that the improper EMT, cardiac progenitor migration, and differentiation are responsible for imidacloprid exposure-induced malformation of heart tube during chick embryo development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Doenças das Valvas Cardíacas/patologia , Coração/efeitos dos fármacos , Coração/embriologia , Imidazóis/toxicidade , Inseticidas/toxicidade , Nitrocompostos/toxicidade , Animais , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Doenças das Valvas Cardíacas/induzido quimicamente , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Laminina/genética , Laminina/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neonicotinoides , Ratos , Regulação para Cima , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo
16.
J Clin Endocrinol Metab ; 101(11): 4189-4194, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27571182

RESUMO

CONTEXT: Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate. OBJECTIVE: Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used. DESIGN: Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group. SETTING: Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included. RESULTS: There were 192 patients (81 males; median age, 51 years; interquartile range [IQR], 42-62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20-377) and 232 mg (91-551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24-42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.


Assuntos
Agonistas de Dopamina/efeitos adversos , Ergolinas/efeitos adversos , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/diagnóstico por imagem , Hiperprolactinemia/tratamento farmacológico , Adulto , Idoso , Cabergolina , Agonistas de Dopamina/administração & dosagem , Ecocardiografia , Ergolinas/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Reino Unido
17.
PLoS One ; 11(8): e0160011, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27487042

RESUMO

There is a risk of misdiagnosis between benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to benfluorex presenting with VHD to have, at the same time, a history of ARF-related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%-2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD.


Assuntos
Depressores do Apetite/efeitos adversos , Fenfluramina/análogos & derivados , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/epidemiologia , Cardiopatia Reumática/induzido quimicamente , Cardiopatia Reumática/epidemiologia , Idoso , Feminino , Fenfluramina/efeitos adversos , França/epidemiologia , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Fatores de Risco
18.
Medicine (Baltimore) ; 95(14): e3172, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27057841

RESUMO

Empirical evidence regarding the association between antidepressants and valvular heart disease (VHD) is scarce.Using Taiwan's National Health Insurance Research database, this nested case-control study assessed the association between antidepressants and VHD in a Chinese population.Among a cohort of patients who used at least 3 prescription antidepressants, 874 cases with VHD and 3496 matched controls (1:4 ratio) were identified. Conditional logistic regression models were used to examine the timing, duration, dose and type of antidepressants use, and the risk of VHD.Current use of antidepressants was associated with a 1.4-fold increase in the risk of VHD (adjusted odds ratio [aOR] 1.44; 95% confidence interval [CI] 1.17-1.77). Among current users, a dose-response association was observed in terms of the cumulative duration and the cumulative antidepressant dose. Significantly higher risks of VHD were observed among the current users of tricyclic antidepressants (aOR 1.40 [1.05-1.87]).We found that the use of antidepressants was associated with a greater risk of VHD and that the risks varied according to different antidepressants.


Assuntos
Antidepressivos/efeitos adversos , Doenças das Valvas Cardíacas/induzido quimicamente , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Doenças das Valvas Cardíacas/epidemiologia , Humanos , Masculino , Medição de Risco , Taiwan , Fatores de Tempo
19.
JACC Cardiovasc Imaging ; 9(3): 230-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26897666

RESUMO

OBJECTIVES: This study assessed the prevalence and associated risk factors for valvular dysfunction (VD) observed in adult lymphoma survivors (LS) after autologous hematopoietic stem cell transplantation (auto-HCT), and to determine whether anthracycline-containing chemotherapy (ACCT) alone in these patients is associated with VD. BACKGROUND: The prevalence of and risk factors for VD in LS after auto-HCT is unknown. Anthracyclines may induce heart failure, but any association with VD is not well-defined. METHODS: This national cross-sectional study included all adult LS receiving auto-HCT from 1987 to 2008 in Norway. VD was defined by echocardiography as either more than mild regurgitation or any stenosis. Observations in LS were compared with a healthy age- and gender-matched (1:1) control group. RESULTS: In total, 274 LS (69% of all eligible) participated. Mean age was 56 ± 12 years, mean follow-up time after lymphoma diagnosis was 13 ± 6 years, and 62% of participants were males. Mean cumulative anthracycline dosage was 316 ± 111 mg/m(2), and 35% had received radiation therapy involving the heart (cardiac-RT). VD was observed in 22.3% of the LS. Severe VD was rare (n = 9; 3.3% of all LS) and mainly aortic stenosis (n = 7). We observed VD in 16.7% of LS treated with ACCT alone (n = 177), corresponding with a 3-fold increased VD risk (odds ratio: 2.9; 95% confidence interval: 1.5 to 5.8; p = 0.002) compared with controls. Furthermore, the presence of aortic valve degeneration was increased in the LS after ACCT alone compared with controls (13.0% vs. 2.9%; p < 0.001). Female sex, age >50 years at lymphoma diagnosis, ≥3 lines of chemotherapy before auto-HCT, and cardiac-RT >30 Gy were identified as independent risk factors for VD in the LS. CONCLUSIONS: In LS, ACCT alone was significantly associated with VD and related to valvular degeneration. Overall, predominantly moderate VD was prevalent in LS, and longer observation time is needed to clarify the clinical significance of this finding.


Assuntos
Doenças das Valvas Cardíacas/epidemiologia , Valvas Cardíacas/fisiopatologia , Linfoma/cirurgia , Transplante de Células-Tronco/efeitos adversos , Sobreviventes , Adulto , Idoso , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/fisiopatologia , Valvas Cardíacas/diagnóstico por imagem , Valvas Cardíacas/efeitos dos fármacos , Humanos , Modelos Logísticos , Linfoma/diagnóstico , Linfoma/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Noruega/epidemiologia , Razão de Chances , Prevalência , Fatores de Risco , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento
20.
Osteoporos Int ; 27(5): 1857-67, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26694594

RESUMO

UNLABELLED: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. INTRODUCTION: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. METHODS: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. RESULTS: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses. CONCLUSIONS: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças das Valvas Cardíacas/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/administração & dosagem , Estudos de Casos e Controles , Bases de Dados Factuais , Difosfonatos/administração & dosagem , Esquema de Medicação , Substituição de Medicamentos , Feminino , Doenças das Valvas Cardíacas/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Medição de Risco/métodos , Sensibilidade e Especificidade , Reino Unido/epidemiologia
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