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2.
Anesth Analg ; 129(3): 882-889, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31425233

RESUMO

BACKGROUND: Evaluation of nociceptive-antinociceptive balance during general anesthesia is still challenging and routinely based on clinical criteria. Analgesic drug delivered may be optimized with parasympathetic tone activity (PTA) monitor. This study compares ketorolac and ketorolac/tramadol balance analgesia using a PTA monitor. METHODS: Pain intensity response was assessed using a 0-100 numerical state scale (PTA) after nociceptive stimuli in pigs under stable sevoflurane anesthesia. Bispectral index, heart rate, noninvasive blood pressure, and respiratory parameters were also measured. Animals were divided into 3 groups: without analgesia, ketorolac, and ketorolac/tramadol. Mean values or mean areas under the curve (AUC) in selected time periods were compared over time and between groups through a mixed-model repeated measures analysis of variance and nonparametric Kruskal-Wallis tests, followed by Bonferroni or Dunn's multiple comparisons. RESULTS: It was observed a significant decrease in the PTA AUC mean value after application of the stimulus in animals treated without analgesia and only with ketorolac. The PTA AUC mean value in the control group was significantly lower than the corresponding mean in ketorolac group. The ketorolac/tramadol group showed the highest PTA AUC mean values, significantly different from those obtained for the other 2 groups, with no significant differences detected over time. Bispectral index means showed no statistically significant differences either over time periods or between different treatment groups. Heart rate showed only a statistically significant increase in AUC mean between without analgesia and ketorolac/tramadol group, in the time period after the stimulus application. Noninvasive blood pressure means showed no statistically significant differences over time and between treatment groups. CONCLUSIONS: This study shows that a low dose combination of ketorolac and tramadol is sufficient to block the pain responses induced with a needle holder in pigs 20 minutes after its administration. The PTA monitor was able to clearly recognize the analgesic level between treatments and may be used to optimize analgesic drug delivered.


Assuntos
Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Cetorolaco/administração & dosagem , Sistema Nervoso Parassimpático/efeitos dos fármacos , Tramadol/administração & dosagem , Animais , Quimioterapia Combinada , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Sistema Nervoso Parassimpático/fisiologia , Distribuição Aleatória , Suínos
3.
Hum Exp Toxicol ; 38(10): 1183-1194, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256679

RESUMO

Heart failure (HF) is a leading cause of hospitalization across the world and is known to cause ill-health and heavy economic losses. In the present study, a rat model of isoproterenol (ISO, 85 mg/kg subcutaneously for two subsequent days) induced HF was developed. ISO induces HF by its direct effect, that is, rise in left ventricular end-diastolic pressure (mechanical) and indirectly by altering the baroreflex (neural), electrocardiography (electrical), and development of oxidative stress and hyperlipidemia (chemical). Fenofibrate, a hypolipidemic drug, which ameliorates myocardial energy metabolism was seen to improve the both ISO-induced oxidative stress and lipid profile and consequently improved Baroreflex Sensitivity (BRS), partial ventricular functions, and cardiac hypertrophy. Therefore, our result suggests that fenofibrate treatment protected the heart by alleviating the ISO-induced effects, that is, neural, mechanical, electrical, and chemical alterations.


Assuntos
Barorreflexo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fenofibrato/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipolipemiantes/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Eletrocardiografia/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , NADPH Oxidases/genética , Ratos Wistar
4.
J Toxicol Sci ; 44(7): 441-457, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270301

RESUMO

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.


Assuntos
Astemizol/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Callithrix , Eletrocardiografia/efeitos dos fármacos , Flecainida/farmacologia , Modelos Animais , Quinidina/farmacologia , Medição de Risco/métodos , Sotalol/farmacologia , Telemetria , Terfenadina/farmacologia , Verapamil/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Astemizol/sangue , Temperatura Corporal/fisiologia , Bloqueadores dos Canais de Cálcio/sangue , Flecainida/sangue , Masculino , Quinidina/sangue , Sotalol/sangue , Terfenadina/sangue , Verapamil/sangue , Bloqueadores do Canal de Sódio Disparado por Voltagem/sangue
5.
Regul Toxicol Pharmacol ; 108: 104433, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362032

RESUMO

PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 µM. PF614 (0.1 and 10 µM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.


Assuntos
Formulações de Dissuasão de Abuso , Analgésicos Opioides/toxicidade , Oxicodona/toxicidade , Pró-Fármacos/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células CACO-2 , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Testes de Mutagenicidade , Proteínas de Neoplasias/metabolismo , Ratos , Regulador Transcricional ERG/metabolismo , Tripsina
6.
Turk Kardiyol Dern Ars ; 47(5): 384-390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31311906

RESUMO

OBJECTIVE: An association between ventricular repolarization parameters (VRPs) and ventricular arrhythmias has been demonstrated in previous studies. However, there are limited data related to a relationship between synthetic cannabinoids (SCs) and VRPs. The aim of this study was to analyze the acute effects of SCs on VRPs using electrocardiogram (ECG) measurements of the T-peak to T-end interval (Tp-e), Tp-e/QT ratio, and Tp-e/corrected QT (QTc) ratio. METHODS: The present study included 58 patients who were admitted to the emergency department who used SCs (SC +) between 2014 and 2016, and 50 healthy control subjects (SC -). The QT and QTc intervals, Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were measured from a 12-lead ECG. These parameters were compared between groups and correlation analysis was performed. RESULTS: The Tp-e and QTc intervals were significantly higher in SC + patients when compared with the SC- group (92.2±177;10.0, 77.4 ±177;9.3, p<0.001; 434.5±177;30.8, 410.9±177;27.3, p<0.001, respectively). Tp-e/QT and Tp-e/QTc ratios were greater in SC + patients in comparison with SC - participants (0.26±177;0.02, 0.22±177;0.02, p<0.001; 0.21±177;0.02, 0.18±177;0.02, p<0.001, respectively). Significant correlations were found between the use of SCs and the Tp-e interval (r=0.610; p<0.001), Tp-e/QT (r=0.655; p<0.001) and Tp-e/ QTc ratios (r=0.437; p<0.001). CONCLUSION: The Tp-e interval, Tp-e/QT and Tp-e/QTc ratios were greater in subjects who used SCs. Therefore, SC users might have an increased risk of ventricular arrhythmia.


Assuntos
Canabinoides/efeitos adversos , Eletrocardiografia/efeitos dos fármacos , Ventrículos do Coração , /efeitos adversos , Estudos de Casos e Controles , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos
7.
Eur J Pharmacol ; 859: 172488, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31233746

RESUMO

Cardiac arrhythmias are among the most important pathologies that lead to sudden death. The discovery of new therapeutic options against arrhythmias with low adverse effects is of paramount importance. Farnesol is found in essential oils with antioxidant, anti-inflammatory and cardioprotective properties. The aim of this work was to investigate the effects of farnesol on the contractile and electrophysiological properties in rat heart and evaluate its antiarrhythmic action. It was evaluated farnesol effects on the left ventricular developed pressure, ECG, potassium (Ik) and L-type Ca2+ currents (ICa,L), action potential, intracellular Ca2+ transient, Ca2+ sparks and waves and reactive oxygen species production. Antiarrhythmic activity of farnesol was determined in vivo and ex vivo. The results showed that 50 µM farnesol did not alter left ventricular developed pressure, heart rate, ECG parameters and intracellular Ca2+ transient but reduced ICa,L. Farnesol reduced action potential duration at 90% repolarization. Notably, farnesol improved arrhythmia score and the incidence of the most severe arrhythmias. Farnesol attenuated the generation of reactive oxygen species, Ca2+ sparks and waves in isolated cardiomyocytes submitted to Ca2+ overload. In conclusion, farnesol has antiarrhythmic effect mediated by reducing of ICa,L and IK along with a decrease of reactive oxygen species production and normalized Ca2+ sparks and waves.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Farneseno Álcool/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Farneseno Álcool/uso terapêutico , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Oxigênio/metabolismo , Potássio/metabolismo , Ratos , Ratos Wistar , Disfunção Ventricular Esquerda/tratamento farmacológico
8.
J Ethnopharmacol ; 242: 112042, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31254629

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, the fruit of a native species that is popularly known as "jabuticaba" (Plinia cauliflora [Mart.] Kausel) is widely consumed fresh or used for the production of liqueur, juice, and jelly. In Brazilian folk medicine, this species is used to treat asthma, throat inflammation, and gastrointestinal and cardiovascular disturbances. However, no previous studies have reported its cardioprotective effects. AIM: To evaluate the possible cardioprotective effects of a hydroethanolic extract of Plinia cauliflora (EEPC) in female rabbits in a model of doxorubicin-induced heart failure. MATERIAL AND METHODS: EEPC was obtained and fractionated by solid phase extraction, and its constituents were determined by liquid chromatography coupled to diode array detector and mass spectrometry (LC-DAD-MS). Thirty female New Zealand rabbits received doxorubicin administration for 6 weeks to induce heart failure. EEPC was orally administered at doses of 75 and 150 mg/kg daily for 42 days. Enalapril (5 mg/kg) was used as a reference cardioprotective drug. At the end of the experimental period, blood pressure and heart rate were recorded. Serum parameters, including lipid profile, troponin, creatinine, nitrotyrosine, malondialdehyde, nitrite, and brain natriuretic peptide, were measured. The electrocardiographic profile and renal vascular reactivity were evaluated. Cardiac histopathology and ventricular morphometry were performed, and the tissue enzymatic antioxidant system was investigated. RESULTS: A total of 37 compounds were detected in EEPC, including organic acids, phenolic acid derivatives, flavonoids, anthocyanins, and hydrolysable tannins (gallotannins and ellagitannins). EEPC treatment induced a cardiorenal protective response, prevented hemodynamic and functional alterations, and prevented ventricle remodeling. These effects were associated with the normalization of creatinine and brain natriuretic peptide levels and modulation of the tecidual antioxidant defense system. CONCLUSION: The present study demonstrated that EEPC may prevent doxorubicin-induced heart failure by modulating the antioxidant defense system, reducing reactive oxygen species-induced damage, preventing alterations of hemodynamic and endothelial function, and preventing damage to the cardiac structure. EEPC, especially at the highest dose tested, may be considered a cardioprotective coadjuvant to prevent doxorubicin-induced cardiotoxicity.


Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Myrtaceae , Extratos Vegetais/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Doxorrubicina , Eletrocardiografia/efeitos dos fármacos , Feminino , Frutas , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/química , Coelhos
9.
Am J Health Syst Pharm ; 76(14): 1059-1070, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31185072

RESUMO

PURPOSE: We aimed to construct a dynamic model for predicting severe QT interval prolongation in hospitalized patients using inpatient electronic health record (EHR) data. METHODS: A retrospective cohort consisting of all adults admitted to 2 large hospitals from January 2012 through October 2013 was established. Thirty-five risk factors for severe QT prolongation (defined as a Bazett's formula-corrected QT interval [QTc] of ≥500 msec or a QTc increase of ≥60 msec from baseline) were operationalized for automated EHR retrieval; upon univariate analyses, 26 factors were retained in models for predicting the 24-hour risk of QT events on hospital day 1 (the Day 1 model) and on hospital days 2-5 (the Days 2-5 model). RESULTS: A total of 1,672 QT prolongation events occurred over 165,847 days of risk exposure during the study period. C statistics were 0.828 for the Day 1 model and 0.813 for the Days 2-5 model. Patients in the upper 50th percentile of calculated risk scores experienced 755 of 799 QT events (94%) allocated in the Day 1 model and 804 of 873 QT events (92%) allocated in the Days 2-5 model. Among patients in the 90th percentile, the Day 1 and Days 2-5 models captured 351 of 799 (44%) and 362 of 873 (41%) QT events, respectively. CONCLUSION: The risk models derived from EHR data for all admitted patients had good predictive validity. All risk factors were operationalized from discrete EHR fields to allow full automation for real-time identification of high-risk patients. Further research to test the models in other health systems and evaluate their effectiveness on outcomes and patient care in clinical practice is recommended.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Síndrome do QT Longo/diagnóstico , Modelos Biológicos , Idoso , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Índice de Gravidade de Doença
10.
Molecules ; 24(10)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109132

RESUMO

Myocardial infarction (MI) remains one of the major causes of mortality around the world. A possible mechanism involved in myocardial infarction is the engagement of Toll-like receptors (TLRs). This study was intended to discover the prospective cardioprotective actions of ß-caryophyllene, a natural sesquiterpene, to ameliorate isoproterenol (ISO)-induced myocardial infarction through HSP-60/TLR/MyD88/NFκB pathway. ß-Caryophyllene (100 or 200 mg/kg/day orally) was administered for 21 days then MI was induced via ISO (85 mg/kg, subcutaneous) on 20th and 21st days. The results indicated that ISO induced a significant infarcted area associated with several alterations in the electrocardiogram (ECG) and blood pressure (BP) indices and caused an increase in numerous cardiac indicators such as creatine phosphokinase (CPK), creatine kinase-myocardial bound (CK-MB), lactate dehydrogenase (LDH), and cardiac tropinine T (cTnT). In addition, ISO significantly amplified heat shock protein 60 (HSP-60) and other inflammatory markers, such as TNF-α, IL-Iß, and NFκB, and affected TLR2 and TLR4 expression and their adaptor proteins; Myeloid differentiation primary response 88 (MYD88), and TIR-domain-containing adapter-inducing interferon-ß (TRIF). On the other hand, consumption of ß-caryophyllene significantly reversed the infarcted size, ECG and BP alterations, ameliorated the ISO elevation in cardiac indicators; it also notably diminished HSP-60, and subsequently TLR2, TLR4, MYD88, and TRIF expression, with a substantial reduction in inflammatory mediator levels. This study revealed the cardioprotective effect of ß-caryophyllene against MI through inhibiting HSP-60/TLR/MyD88/NFκB signaling pathways.


Assuntos
Produtos Biológicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase/metabolismo , Eletrocardiografia/efeitos dos fármacos , Isoproterenol/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley
11.
Pesqui. vet. bras ; 39(5): 324-331, May 2019. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1012747

RESUMO

This study aimed to evaluate the effect of treatment with equine chorionic gonadotrophin (eCG) on the follicular dynamics and function of crossbred cows with different circulating progesterone (P4) concentrations during synchronization of ovulation in a fixed-time artificial insemination (FTAI) protocol. To this end, 30 crossbred cows were submitted to a pre-synchronization protocol to ensure that all of them presented corpus luteum (CL) at the beginning of the protocol, and were evaluated by transrectal ultrasonography (TRUS) to verify the presence of CL. After that, the animals underwent an ovulation synchronization protocol and evaluation of follicular dynamics and vascularization by B-mode and power-Doppler ultrasound (US). High plasma P4 concentrations at the time of ovulation synchronization negatively influenced follicle diameter on day 10 (D10), preovulatory follicle diameter, and preovulatory follicle wall vascularization area (p<0.05). Cows with high P4 concentration at the time of ovulation synchronization that were treated with eCG showed follicle diameter on D10 and preovulatory follicle diameter and wall vascularization area (p>0.05) similar to those of animals with low P4 concentration at the time of ovulation synchronization. Therefore, high P4 concentrations at the time of ovulation synchronization negatively influence follicular diameter and vascularization, and eCG can be used as a strategy to favor better follicular and luteal response in crossbred cows with high P4 concentrations submitted to an FTAI protocol.(AU)


Objetivou-se neste estudo avaliar o efeito do tratamento com gonadotrofina coriônica equina (eCG) sobre a dinâmica e função folicular em fêmeas mestiças com diferentes concentrações circulantes de P4 durante a sincronização da ovulação em um protocolo de IATF. Para tanto, foram utilizadas 30 fêmeas mestiças e submetidas a um protocolo de pré-sincronização para garantir que todos os animais apresentassem corpo lúteo (CL) no início do protocolo, sendo avaliadas por ultrassonografia (US) transretal para a verificação da presença ou não de CL. Em seguida foram submetidas a um protocolo de sincronização da ovulação e avaliação da dinâmica e vascularização folicular por ultrassonografia (US) em modo B e Doppler colorido. Altas concentrações de P4 no momento da sincronização da ovulação impactaram negativamente no diâmetro do folículo no D10, o diâmetro do folículo pré-ovulatório e na área de vascularização da parede do folículo pré-ovulatório (P<0,05). As vacas com alta concentração de P4 no momento da sincronização da ovulação e que foram tratadas com eCG apresentaram diâmetro do folículo no D10 e no diâmetro e a área de vascularização da parede do folículo pré-ovulatório (P>0,05), semelhantes às vacas que com baixa concentração de P4 no momento da sincronização da ovulação. Conclui-se que elevadas concentrações de P4 no momento da sincronização da ovulação impactam negativamente no diâmetro e vascularização folicular e que o eCG pode ser utilizado como uma estratégia para favorecer uma melhor resposta folicular e luteal em fêmeas mestiças com altas concentrações de P4 submetidas a um protocolo de IATF.(AU)


Assuntos
Animais , Feminino , Bovinos , Progesterona/análise , Inseminação Artificial/veterinária , Eletrocardiografia/efeitos dos fármacos , Ovulação
12.
Mult Scler Relat Disord ; 32: 30-32, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029055

RESUMO

Standard therapy for a relapse of multiple sclerosis is a high dose pulse corticosteroid therapy. Cardiovascular adverse events ranging from palpitations to serious arrhythmias like atrial fibrillation and ventricular tachycardia have been associated with this treatment. The underlying mechanism behind the development of atrial fibrillation and treatment of multiple sclerosis relapse with steroids is still unclear. In this case, a 27-year-old male with multiple sclerosis is presented who developed atrial fibrillation on two occasions following two consecutive treatments with high dose methylprednisolone for the treatment of multiple sclerosis relapse. Extensive work-up revealed mild sympathetic autonomic system dysfunction. Based on this case and previous studies, we propose that a disturbed function of the autonomic system increases the risk of atrial fibrillation and/or other arrhythmias in people with multiple sclerosis.


Assuntos
Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/diagnóstico , Metilprednisolona/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Fibrilação Atrial/fisiopatologia , Eletrocardiografia/efeitos dos fármacos , Humanos , Masculino , Metilprednisolona/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Pulsoterapia/efeitos adversos , Recidiva , Resultado do Tratamento
13.
Am J Ther ; 26(3): e417-e420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946048

RESUMO

BACKGROUND: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population. AREAS OF UNCERTAINTY: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile. SOURCES: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature. RESULTS: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible. CONCLUSIONS: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Indóis/administração & dosagem , Síndrome do Intestino Irritável/tratamento farmacológico , Agonistas do Receptor 5-HT4 de Serotonina/administração & dosagem , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos como Assunto , Aprovação de Drogas/legislação & jurisprudência , Eletrocardiografia/efeitos dos fármacos , Humanos , Indóis/efeitos adversos , Agonistas do Receptor 5-HT4 de Serotonina/efeitos adversos , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
14.
Eur J Pharmacol ; 854: 159-166, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30991047

RESUMO

After acute myocardial infarction (AMI), reactive oxygen species and oxidative stress have important roles in the progression to heart failure. As a therapeutic alternative, thyroid hormones (TH) revealed cardioprotective effects after AMI, including decreasing oxidative stress. Carvedilol beta-blocker, already used in the clinical treatment of AMI, also mitigate cardiac pathological remodelling. This study assessed the effects of post-AMI carvedilol and TH co-administration on oxidative stress and cardiac function as well as whether those effects were synergistic. Male Wistar rats were divided into five groups: sham-operated (SHAM), infarcted (MI), infarcted + TH (MI + TH), infarcted + carvedilol (MI + C) and infarcted + C + TH (MI + C + TH). Two days post-surgery, the SHAM and MI groups received saline, and treated groups received their respective treatments by gavage for 12 days. The animals were submitted to echocardiographic evaluation, ventricular catheterization and euthanized for heart collection to perform oxidative stress analysis. Treated groups improved for ejection fraction compared to the MI group. Carvedilol decreased the positive chronotropic TH effects in the MI + C + TH group. The MI and MI + C groups had increased reactive oxygen species and reduced sulfhydryl levels. Carvedilol and TH co-administration showed synergic effects in the MI + C + TH group, reducing reactive oxygen species levels and improving GSH/GSSG ratio. Moreover, co-treatment attenuated NADPH oxidase activity in the MI group. Therefore, this study showed for the first time that carvedilol and TH co-administration may improve redox balance and cardiac function after AMI. Such co-administration could represent a therapeutic strategy capable of preventing cardiac dysfunction and redox unbalance after AMI.


Assuntos
Carvedilol/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Antioxidantes/metabolismo , Sinergismo Farmacológico , Eletrocardiografia/efeitos dos fármacos , Dissulfeto de Glutationa/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , NADPH Oxidases/metabolismo , Oxirredução , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Tireotropina/sangue
15.
J Affect Disord ; 250: 341-345, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877856

RESUMO

BACKGROUND: Although the US Food and Drug Administration (FDA) recommended upper limits for citalopram dosing in older adults due to risk of corrected-QT (QTc) prolongation, which was adopted, and extended to escitalopram by Health Canada, the scientific basis is unclear. The objective of this study was to assess the relationship between citalopram/escitalopram dosages and QTc interval in a real-world geriatric setting. METHODS: We reviewed electronic health records at a university-affiliated geriatric health care center, over a 7-year period, to identify patients prescribed citalopram and escitalopram, who had an ECG within 90 days of initiation or dosage change. Linear regression analyses were conducted to assess the relationship between antidepressant dosage and QTc interval. RESULTS: 137 patients were identified (citalopram=97, escitalopram=40). No association was found between citalopram, escitalopram and QTc, in unadjusted or adjusted analyses. Among covariates, older age was significantly associated with QTc prolongation in the escitalopram group. LIMITATIONS: Limitations to the current study include its retrospective design and the small sample size. CONCLUSIONS: These data do not support the FDA or Health Canada's recommended maximum dosages of citalopram or escitalopram in the elderly. Therefore, for patients already on higher doses of these medications, the risk of QTc prolongation may not always outweigh the risk of dose lowering, such as relapse. Until larger prospective studies become available, the decision to comply or not with these federal agencies' recommendations should be weighed on an individual basis, taking into consideration all potential risk factors.


Assuntos
Citalopram/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Inibidores de Captação de Serotonina/efeitos adversos , Idoso , Arritmias Cardíacas , Citalopram/administração & dosagem , Eletrocardiografia/efeitos dos fármacos , Registros Eletrônicos de Saúde , Feminino , Serviços de Saúde para Idosos , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Inibidores de Captação de Serotonina/administração & dosagem
17.
Artigo em Inglês | MEDLINE | ID: mdl-30779962

RESUMO

Rat telemetry is widely used for biomedical research purposes and is used routinely in early pre-clinical drug development to screen for the potential cardiovascular risk of candidate drugs. Historically, these studies have been conducted in individually housed conditions which can impact significantly on an animal's welfare. Here we present data from a survey of pharmaceutical companies and contract research organisations to define current industry practices relating to the housing of rats during telemetry studies and to expand and complement a similar project in non-rodents. Results of the survey showed that 75% of respondents socially house rats on non-recording days of telemetry studies, whereas on recording days only 46% of respondents socially house the animals. When social housing is used on rat telemetry studies, rats are usually housed with an unrecorded companion animal. We also present and compare data from a telemetry study in standard individually ventilated cages (IVCs) with a study using new double-decker IVCs, both conducted using a companion animal approach. Telemetry signals were successfully collected from the double-decker IVCs without a loss of signal quality whilst offering a more spacious environment that allowed the animals to exhibit natural behaviours including full upright posture. Cardiovascular responses following pharmacological intervention with verapamil were similar when assessed in the standard and double-decker cages. Power analysis was conducted on pooled data from the studies in socially housed animals with preliminary results showing the power of detection of drug-induced effects is equivalent to previously published data in individually housed rats. This illustrates that telemetry recordings can be made from rats in socially housed conditions within standard or larger double-decker cages for the for the collection of cardiovascular telemetry data.


Assuntos
Coração/efeitos dos fármacos , Abrigo para Animais , Telemetria/métodos , Bem-Estar do Animal , Animais , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Ratos , Meio Social , Isolamento Social , Verapamil/farmacologia
18.
Toxicol Mech Methods ; 29(6): 397-402, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30676175

RESUMO

Background: Many studies have demonstrated that the water extracts and low-molecular-weight peptide (LMWP) of the Musca domestica larvae contain significant biological activity. However, the cardiovascular and respiratory safety evaluations of LMWP are yet to be sufficiently investigated. Aim: This study focused on the cardiovascular and respiratory safety evaluations of the M. domestica larvae LMWP in beagle dogs. Methods: Direct cardiovascular and respiratory effects of three different doses of the M. domestica larvae LMWP were investigated following only once oral administration in conscious telemetered dogs, whereby ECG, arterial pressure, and respiratory data were collected using the Data Science International telemetric system. Results: The PR, QT, and QTcf intervals were significantly shortened in the medium-dose LMWP treatment group at 3 h after drug administration. Furthermore, no significant differences were observed in any of the corresponding indexes of other treatment groups at different time points compared to those of the control group. P wave, ST segment, R wave, systolic pressure, diastolic pressure, and mean pressure were significantly different, although these differences had no significant dose-effect relationship. Respiratory frequency significantly increased in the medium-dose LMWP treatment group at 8 h after drug administration compared to that of the control group. Respiratory rate and tidal volume showed no significant differences at varying time points among all LMWP treatment groups. Conclusions: No toxicological effects related to cardiovascular and respiratory safety in beagle dogs were observed at any dose level of the M. domestica larvae LMWP.


Assuntos
Produtos Biológicos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Moscas Domésticas/química , Larva/química , Peptídeos/toxicidade , Respiração/efeitos dos fármacos , Administração Oral , Animais , Produtos Biológicos/isolamento & purificação , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Masculino , Medicina Tradicional Chinesa , Peso Molecular , Peptídeos/isolamento & purificação , Telemetria
19.
Pharmacopsychiatry ; 52(1): 38-43, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29466824

RESUMO

INTRODUCTION: Many antidepressants cause QT prolongation but the classification of cardiac risk of these drugs varies markedly in different published lists. This retrospective study analyzed the correlation of QTc time with amitriptyline and venlafaxine serum level in elderly psychiatric inpatients. METHODS: Elderly inpatients aged≥65 years for whom venlafaxine or amitriptyline serum level had been measured were selected retrospectively from a therapeutic drug monitoring database and screened for an electrocardiogram measurement at the time of blood withdrawal. The correlation of amitriptyline or venlafaxine serum levels with QTc time was examined by using Pearson's correlation analysis. RESULTS: Amitriptyline serum levels (n=11) correlated significantly with QTc time (r=0.918, p<0.001, CI 95%). Venlafaxine serum levels (n=27) also correlated significantly with QTc time (r=0.382, p<0.05, CI 95%). DISCUSSION: Amitriptyline and venlafaxine induce QT prolongation depending on drug concentrations in blood. Its extent, however, is very low when drug serum levels are within the therapeutic range. Future pharmacokinetic studies that correlate drug serum level and QT time should classify the cardiac risk of drugs based on the grade of the regression line in relation to the therapeutic range.


Assuntos
Amitriptilina/efeitos adversos , Eletrocardiografia/efeitos dos fármacos , Síndrome do QT Longo/sangue , Cloridrato de Venlafaxina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Amitriptilina/sangue , Antidepressivos/efeitos adversos , Antidepressivos/sangue , Bases de Dados Factuais , Feminino , Humanos , Pacientes Internados , Masculino , Estudos Retrospectivos , Cloridrato de Venlafaxina/sangue
20.
Drug Saf ; 42(3): 415-426, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30255348

RESUMO

INTRODUCTION: In studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR. When data-specific corrections are designed, tests of their validity are needed. The proposed tests include zero correlations between QTc and corresponding RR values in the complete study data (pooling on-treatment and off-treatment interval measurements). OBJECTIVE: To document that this approach is potentially highly misleading, a statistical modeling study was conducted based on the full profiles of QT/RR data of 523 healthy subjects-254 females, mean age 33.5 years. METHODS: In each of the subjects, 50 baseline QT/RR readings were selected to model baseline data. In repeated experiments, groups of ten and 50 subjects were randomly selected and drug-induced HR increases between 0 and 25 beats per minute combined with QTc changes between - 20 and + 20 ms were modeled. In each experiment, subject-specific as well as population-specific HR corrections were designed so that the QTc interval data were uncorrelated to the corresponding RR interval data. RESULTS: The simulation experiments showed that when zero correlations of QTc data with RR data are combined with more than trivial HR increases, the HR corrections are substantially biased and underestimate or fully eliminate any drug-induced QTc interval changes. This result is in full agreement with theoretical considerations of HR correction principles. CONCLUSIONS: The lack of correlation of QTc versus RR durations including on-treatment data does not prove any validity of HR corrections. Correlations of QTc versus RR in study data pooling on- and off-drug measurements should not be used to prove the appropriateness of HR corrections.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Modelos Cardiovasculares , Modelos Estatísticos , Adulto , Feminino , Frequência Cardíaca/fisiologia , Humanos , Síndrome do QT Longo/diagnóstico , Masculino , Sensibilidade e Especificidade , Especificidade da Espécie
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