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1.
Drug Deliv ; 26(1): 147-157, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30822171

RESUMO

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Fluorcarbonetos/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Água/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/metabolismo , Fluorcarbonetos/metabolismo , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/metabolismo , Masculino , Fenilpropionatos/administração & dosagem , Fenilpropionatos/metabolismo , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/metabolismo , Piridazinas/administração & dosagem , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Água/metabolismo
2.
Lancet Psychiatry ; 6(1): 35-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528676

RESUMO

BACKGROUND: Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users. METHODS: We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18-55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2:1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656. FINDINGS: Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11·00 [95% CI 7·78-15·57] vs 6·04 [4·43-8·24]; difference 4·96 [0·71-9·21]; padj=0·048; second day of treatment 11·74 [8·28-16·66] vs 6·02 [4·28-8·47]; difference 5·73 [1·13-10·32]; padj=0·035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1·27 joints per day [95% CI 0·82-1·97] vs 0·40 [0·25-0·62]; difference 0·88 [0·29-1·46]; p=0·0003) and lower urinary THC-COOH concentrations (mean 657·92 ng/mL [95% CI 381·60-1134·30] vs 265·55 [175·60-401·57]; difference 392·37 [17·55-767·18)]; p=0·009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events. INTERPRETATION: PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. FUNDING: United States National Institute of Drug Abuse (NIDA).


Assuntos
Cannabis , Abuso de Maconha/tratamento farmacológico , Piridazinas/administração & dosagem , Síndrome de Abstinência a Substâncias , Ureia/análogos & derivados , Adolescente , Adulto , Amidoidrolases , Método Duplo-Cego , Humanos , Masculino , Fumar Maconha , Pessoa de Meia-Idade , Resultado do Tratamento , Ureia/administração & dosagem , Adulto Jovem
3.
Drug Des Devel Ther ; 12: 1347-1352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29861626

RESUMO

Aim: The aim of this study was to investigate the effects of levosimendan and thymoquinone (TQ) on lung injury after myocardial ischemia/reperfusion (I/R). Materials and methods: Twenty-four Wistar albino rats were included in the study. The animals were randomly assigned to 1 of 4 experimental groups. In Group C (control group), left anterior descending artery was not occluded or reperfused. Myocardial I/R was induced by ligation of the left anterior descending artery for 30 min, followed by 2 h of reperfusion in the I/R, I/R-levosimendan (24 µg/kg) (IRL) group, and I/R-thymoquinone (0.2 mL/kg) (IRTQ) group. Tissue samples taken from the lungs of rats were histochemically stained with H&E and immunohistochemically stained with p53, Bcl 2, Bax, and caspase 3 primer antibodies. Results: Increased expression of p53 and Bax was observed (4+), especially in the I/R group. In IRTQ and IRL groups, expression was also observed at various locations (2+, 3+). H&E staining revealed that that the lungs were severely damaged and the walls of the alveoli were too thick, the number of areas examined was increased during the evaluation. Caspase 3 expression was observed to be at an (1+, 2+) intensity that was usually weak and diffuse in multiple areas. Bcl 2 was not found to be expressed in any of the tissues. H&E staining revealed that that the lungs were severely damaged in the I/R group, with the walls of the channels and alveoli thickened and edematous, and also an intense inflammatory cell migration was observed. Immunohistochemical staining was more prominent in inflammatory areas and structures around the terminal bronchioles. Conclusion: The findings in our study have shown that administration of levosimendan and TQ during I/R increases expression of caspase 3, p53, and Bax in lung tissue and has a protective effect on lung as distant organ. We suggest that findings of this study be elucidated with further large-scale clinical studies.


Assuntos
Benzoquinonas/uso terapêutico , Hidrazonas/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Piridazinas/uso terapêutico , Animais , Benzoquinonas/administração & dosagem , Hidrazonas/administração & dosagem , Imuno-Histoquímica , Injeções Intraperitoneais , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Piridazinas/administração & dosagem , Ratos , Ratos Wistar , Simendana , Proteína X Associada a bcl-2/análise , Proteína X Associada a bcl-2/biossíntese
5.
J Card Surg ; 33(6): 322-329, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29785788

RESUMO

PURPOSE: We sought to determine the impact of levosimendan on mortality following cardiac surgery based on large-scale randomized controlled trials (RCTs). METHODS: We searched PubMed, Web of Science, Cochrane databases, and ClinicalTrials.gov for RCTs published up to December 2017, on levosimendan for patients undergoing cardiac surgery. RESULTS: A total of 25 RCTs enrolling 2960 patients met the inclusion criteria; data from 15 placebo-controlled randomized trials were included for meta-analysis. Pooled analysis showed that the all-cause mortality rate was 6.4% (71 of 1106) in the levosimendan group and 8.4% (93 of 1108) in the placebo group (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.55-1.04; P = 0.09). There were no significant differences between the two groups in the rates of myocardial infarction (OR: 0.91; 95% CI, 0.68-1.21; P = 0.52), serious adverse events (OR: 0.84; 95% CI, 0.66-1.07; P = 0.17), hypotension (OR: 1.69; 95% CI, 0.94-3.03; P = 0.08), and low cardiac output syndrome (OR: 0.47; 95% CI, 0.22-1.02; P = 0.05). CONCLUSION: Levosimendan did not result in a reduction in mortality in adult cardiac surgery patients. Well designed, adequately powered, multicenter trials are necessary to determine the role of levosimendan in adult cardiac surgery.


Assuntos
Baixo Débito Cardíaco/mortalidade , Baixo Débito Cardíaco/prevenção & controle , Procedimentos Cirúrgicos Cardíacos , Bases de Dados Bibliográficas , Hidrazonas/administração & dosagem , Inibidores de Fosfodiesterase/administração & dosagem , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Piridazinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Simendana
6.
Expert Opin Drug Saf ; 17(6): 623-628, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29845876

RESUMO

INTRODUCTION: In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment. Areas covered: Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported. Limited attention to long-term events or more in general, to the impact of AEs on patient quality of life (QoL), remains a problem. Ponatinib is active against all BCR-ABL1 mutants, including T315I, and is widely used to treat patients who developed resistance to other TKIs in any CML phase; however, only limited data is available on the possible role of ponatinib for intolerant patients. Expert opinion: We review the different definitions of intolerance used in sponsored trials and in clinical practice, and we discuss how such definitions impact on the management of AEs. We summarize how to evaluate QoL during treatment with TKIs and how to include ponatinib among possible option for intolerant patients.


Assuntos
Imidazóis/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridazinas/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Qualidade de Vida , Fatores de Tempo , Resultado do Tratamento
7.
Ann Card Anaesth ; 21(2): 123-128, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29652271

RESUMO

Background: Off-pump coronary artery bypass surgery (OPCAB) is often complicated by hemodynamic instability, especially in patients with prior left ventricular (LV) dysfunction and appropriate choice of inotrope plays a vital role in perioperative management of these patients. Aim and Objective: To study hemodynamic effects and immediate outcome of prophylactic infusion of levosimendan in patients with the LV dysfunction undergoing OPCAB surgery and whether this strategy helps in successful conduct of OPCAB surgery. Materials and Methods: After Institutional Ethics Committee approval, 60 patients posted for elective OPCAB surgery were randomly divided into two groups (n = 30 each). Patients with the LV ejection fraction <30% were included. Study group was started on injection levosimendan (@ 0.1 µg/kg/min) in the previous night before surgery and continued for 24 h including intraoperative period. Hemodynamic monitoring included heart rate, invasive blood pressure, cardiac index (CI), pulmonary capillary wedge pressure (PCWP), pulse oximetry, and arterial blood gases with serum lactates at as T0 (baseline), T1 (15 min after obtuse marginal and/or PDA anastomoses), T2 (at end of surgery), T3 (6 h after surgery in Intensive Care Unit [ICU]), T4 (12 h after surgery), and T5 (24 h after surgery in ICU). Vasopressor was added to maintain mean arterial pressure >60 mmHg. Chi-square/Fisher's exact/Mid P exact test and Student's t-tests were applied for categorical and continuous data. Results: CI was greater and PCWP reduced significantly in Group L during intraoperative and early postoperative period. Serum lactate concentration was lower in patients pretreated with levosimendan. Incidence of postoperative atrial fibrillation (POAF) (36.6 vs. 6.6%; P = 0.01), low cardiac output syndrome (LCOS) (30% vs. 6%; P = 0.02), and acute kidney injury (23.3% vs. 6.7%; P = 0.04) was less in Group L. Three patients (10%) in control group required conversion to cardiopulmonary bypass (CPB) as compared to none in the study group. There was no difference regarding ICU or hospital stay and mortality in both groups. Conclusion: Preoperative levosimendan helps in successful conduct of OPCAB and reduces the incidence of LCOS, POAF, conversion to CPB, and requirement of intra-aortic balloon pump.


Assuntos
Lesão Renal Aguda/prevenção & controle , Ponte de Artéria Coronária sem Circulação Extracorpórea/métodos , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Vasoconstritores/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/cirurgia , Adulto , Idoso , Débito Cardíaco/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hidrazonas/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Assistência Perioperatória , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Pressão Propulsora Pulmonar , Piridazinas/administração & dosagem , Simendana , Vasoconstritores/administração & dosagem
8.
Drug Dev Ind Pharm ; 44(6): 1001-1011, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29382236

RESUMO

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD50). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.


Assuntos
Daucus carota/química , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Administração Oral , Disponibilidade Biológica , Portadores de Fármacos , Liberação Controlada de Fármacos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/química , Piridazinas/administração & dosagem , Piridazinas/química , Solubilidade
9.
BMC Cancer ; 18(1): 43, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29316898

RESUMO

BACKGROUND: The circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body. MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system. Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use. Here, we test if timed application of the specific p38 MAPK inhibitor VX-745 reduces glioma cell invasive properties in vitro. METHODS: The levels and rhythmic accumulation of active phosphorylated p38 MAPK in different cell lines were determined by western blots. Rhythmic luciferase activity from clock gene luciferase reporter cells lines was used to test the effect of p38 MAPK inhibition on clock properties as determined using the damped sine fit and Levenberg-Marquardt algorithm. Nonlinear regression and Akaike's information criteria were used to establish rhythmicity. Boyden chamber assays were used to measure glioma cell invasiveness following time-of-day-specific treatment with VX-745. Significant differences were established using t-tests. RESULTS: We demonstrate the activity of p38 MAPK cycles under control of the clock in mouse fibroblast and SCN cell lines. The levels of phosphorylated p38 MAPK were significantly reduced in clock-deficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Inhibition of p38 MAPK activity with VX-745 led to cell-type-specific period changes in the molecular clock. In addition, phosphorylated p38 MAPK levels were rhythmic in HA glial cells, and high and arrhythmic in invasive IM3 glioma cells. We show that inhibition of p38 MAPK activity in IM3 cells at the time of day when the levels are normally low in HA cells under control of the circadian clock, significantly reduced IM3 invasiveness. CONCLUSIONS: Glioma treatment with p38 MAPK inhibitors may be more effective and less toxic if administered at the appropriate time of the day.


Assuntos
Proteínas CLOCK/genética , Relógios Circadianos/genética , Glioblastoma/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Linhagem da Célula/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Luciferases , Camundongos , Invasividade Neoplásica/genética , Fosforilação , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
10.
Int J Cardiol ; 251: 22-31, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29126653

RESUMO

BACKGROUND: Several studies suggested beneficial effects of perioperative levosimendan on postoperative outcome after cardiac surgery. However, three large randomized controlled trials (RCTs) have been recently published and presented neutral results. We performed a systematic review with meta-analysis and trial sequential analysis (TSA) to assess benefits and harms of perioperative levosimendan therapy in cardiac surgery. METHODS: Electronic databases were searched up to September 2017 for RCTs on preoperative levosimendan versus any type of control. The Cochrane methodology was employed. We calculated odds ratio (OR) or Risk Ratio (OR) and 95% confidence interval (CI) using fixed-effects meta-analyses and we further performed TSA. RESULTS: We included data from 40 RCTs and 4246 patients. Pooled analysis of 5 low risk of bias trials (1910 patients) showed no association between levosimendan and mortality (OR 0.86 [95% CI, 0.62, 1.18], p=0.34, TSA inconclusive), acute kidney injury, need of renal replacement therapy, myocardial infarction, ventricular arrhythmias, and serious adverse events, but an association with higher incidence of supraventricular arrhythmias (RR 1.11 [95% CI, 1.00, 1.24], p=0.05, TSA inconclusive) and hypotension (RR 1.15 [95% CI, 1.01, 1.30], p=0.04, TSA inconclusive). Analysis including all 40 trials found that levosimendan was associated with lower postoperative mortality (OR 0.56 [95% CI, 0.44, 0.71], p<0.00001, TSA conclusive), acute kidney injury, and renal replacement therapy, and higher incidence of hypotension. CONCLUSIONS: There is not enough high-quality evidence to neither support nor discourage the systematic use of levosimendan in cardiac surgery.


Assuntos
Antiarrítmicos/administração & dosagem , Procedimentos Cirúrgicos Cardíacos/métodos , Hidrazonas/administração & dosagem , Assistência Perioperatória/métodos , Piridazinas/administração & dosagem , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Simendana
11.
Eur Heart J Acute Cardiovasc Care ; 7(4): 321-329, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28045338

RESUMO

BACKGROUND: Echocardiography is recommended for assessment of left ventricular systolic function in patients with acute heart failure but few randomised trials have validated techniques like tissue Doppler (TDI) and speckle tracking (STE) in patients with acute heart failure following ST-elevation myocardial infarction. METHODS: This was a substudy from the LEAF (LEvosimendan in Acute heart Failure following myocardial infarction) trial (NCT00324766 ), which randomised 61 patients developing acute heart failure, including cardiogenic shock, within 48 hours after ST-elevation myocardial infarction, double-blind to a 25-hour infusion of levosimendan or placebo. TDI-derived systolic mitral annulus velocity (S'), STE-derived global longitudinal strain (Sl) and strain rate (SRl) were measured at baseline, day 1, day 5 and after 42 days. RESULTS: Datasets rejected for analyses were 2% (TDI) and 17% (STE). S' increased by 23% in the levosimendan group versus 8% in the placebo group from baseline to day 1 ( p= 0.011) and by 30% vs. 3% from baseline to day 5 ( p <0.0005). Significant, but less pronounced, improvements in global Sl ( p = 0.025 and p = 0.032) and in global SRl ( p = 0.046 and p = 0.001) in favour of levosimendan were also present. CONCLUSION: S' by TDI and STE-derived Sl and SRl were sensitive indices for changes in left ventricular systolic function related to treatment with levosimendan. However, S' by TDI was more feasible and sensitive and might be preferred for assessment of changes in left ventricular systolic function in critically ill patients with acute heart failure receiving inotropic therapy.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Ecocardiografia Doppler em Cores/métodos , Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/fisiopatologia , Hidrazonas/administração & dosagem , Valva Mitral/fisiopatologia , Piridazinas/administração & dosagem , Função Ventricular Esquerda/fisiologia , Doença Aguda , Idoso , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Estudos de Viabilidade , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Valva Mitral/diagnóstico por imagem , Reprodutibilidade dos Testes , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Simendana , Sístole , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos
12.
Clin Hemorheol Microcirc ; 68(1): 83-87, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29036801

RESUMO

There is increasing evidence in the literature that preoperative treatment with levosimendan optimizes cardiopulmonary haemodynamics in patients scheduled for the implantation of a Left Ventricular Assist Device (LVAD). The present case report describes changes in sublingual microcirculation using incident dark field video microscopy in a patient, who received a continuous infusion of 0.5 mg/h levosimendan 12 h before LVAD implantation. Despite no evident macrohaemodynamic or metabolic changes, there was a dramatic reduction in total vessel density and perfused vessel density suggesting a deterioration of microcirculation according to the consensus conference criteria in vessels smaller than 20 µm in diameter. However, the microcirculation of all visible vessels (regardless of diameter) was maintained. This potential misinterpretation is explained by a levosimedan-induced vasodilation and the subsequent reduction of the percentage of vessels with a diameter smaller than 20 µm. Physicians should carefully consider this pitfall of applying the consensus conference criteria in vasodilator-treated patients.


Assuntos
Hidrazonas/uso terapêutico , Microcirculação/efeitos dos fármacos , Piridazinas/uso terapêutico , Vasodilatadores/uso terapêutico , Administração Sublingual , Hemodinâmica , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/farmacologia , Masculino , Pessoa de Meia-Idade , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Simendana , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia
13.
Am J Cardiovasc Drugs ; 18(1): 49-58, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28819767

RESUMO

BACKGROUND: Acute kidney injury (AKI) occurs frequently after cardiac surgery and has been associated with increased hospital length of stay, mortality, and costs. OBJECTIVE: We aimed to evaluate the efficacy of pharmacologic strategies for preventing AKI after cardiac surgery. METHODS: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) up to 6 May 2017 and the reference lists of relevant articles about trials. The outcome was the occurrence of AKI. This is the first network meta-analysis of the different prevention strategies using Bayesian methodology. RESULTS: The study included 63 articles with 19,520 participants and evaluated the effect of ten pharmacologic strategies to prevent AKI in patients undergoing cardiac surgery. Compared with placebo, the odds ratio (OR) for the occurrence of AKI was 0.24 [95% confidence interval (CI) 0.16-0.34] with natriuretic peptide, 0.33 (95% CI 0.14-0.70) with fenoldopam, 0.54 (95% CI 0.31-0.84) with dexmedetomidine, 0.56 (95% CI 0.29-0.95) with low-dose erythropoietin, 0.63 (95% CI 0.43-0.88) with levosimendan, 0.76 (95% CI 0.52-1.10) with steroids, 0.83 (95% CI 0.48-1.40) with high-dose erythropoietin, 0.85 (95% CI 0.64-1.14) with N-acetylcysteine, 0.96 (95% CI 0.69-1.29) with sodium bicarbonate, and 1.05 (95% CI 0.70-1.41) with statins. The surface under the cumulative ranking curve probabilities indicated that natriuretic peptide was the best treatment therapy and that fenoldopam ranked second. CONCLUSIONS: Natriuretic peptide is probably the preferred pharmacologic strategy to prevent AKI in adult patients undergoing cardiac surgery, especially in those at high risk of AKI.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/tendências , Lesão Renal Aguda/epidemiologia , Venenos Elapídicos/administração & dosagem , Humanos , Hidrazonas/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Peptídeo Natriurético Tipo C/administração & dosagem , Piridazinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Simendana , Resultado do Tratamento
14.
J Vet Pharmacol Ther ; 41(1): 105-116, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28649790

RESUMO

The objective of the study was to investigate the safety of a combination tablet of benazepril and pimobendan, Fortekor PLUS® , in a randomized, blinded, parallel-group design study in healthy adult beagle dogs. The test article, Fortekor PLUS® tablets, was administered orally twice daily for 6 months at one, two, and four times the highest recommended dosage of 0.5 mg/kg benazepril hydrochloride/0.25 mg/kg pimobendan (four males and four females per group). An additional control group was sham-dosed. Fortekor PLUS® did not induce any treatment-related effects on body weight, food consumption, neurological, ophthalmologic or physical assessments over the 6-month treatment period. The test article was possibly associated with an increased frequency of occasional vomiting. Fortekor PLUS® was associated with small, but significant, increases in heart rate and reductions in PR and QT intervals, which were assessed by electrocardiography. These effects were most probably related to reflex tachycardia secondary to reduced systemic blood pressure. Statistically significant changes in some clinical pathology variables were noted after test article administration, but were considered to be of no clinical relevance as values remained within reference ranges and/or were not dose-dependent. No treatment-related macroscopic or microscopic findings were observed. In conclusion, Fortekor PLUS® tablets were well tolerated in healthy adult dogs when administered at one, two, and four times the highest recommended dosage for 6 months.


Assuntos
Benzazepinas/administração & dosagem , Piridazinas/administração & dosagem , Administração Oral , Animais , Benzazepinas/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Piridazinas/efeitos adversos
15.
Clin Respir J ; 12(4): 1518-1525, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28862394

RESUMO

BACKGROUND: Despite using vasoactive and pulmonary hypertension (PH) specific therapies, the in-hospital mortality of severe PH with right heart failure (RHF) is high. We conducted a prospective analysis evaluating the efficacy and safety of levosimendan in PH patients with severe acute RHF. METHODS: Forty-five PH patients hospitalized between January 2016 and November 2016 were recruited into a single arm, prospective, open-label study. Levosimendan was administered at the rate of .05-0.1 µg/kg/min, up to a total dose of 12.5 mg. The primary endpoints were changes of World Health Organization Function Class (WHO-FC) and Borg dyspnoea scores. Secondary endpoints included changes in 6-min walk distance (6-MWD), biochemical markers and right heart structure and function together with adverse events on day 7 and incidence of major cardiovascular events (death or readmission due to RHF) on day 30. RESULTS: Forty-five PH patients were enrolled. On the 7th day after levosimendan infusion, seven out of 13 PH patients with WHO-FC IV improved by one class (P = .008). Borg dyspnoea scores, 6-MWD and NT-proBNP improved significantly (P < .001). Compared with baseline, the right atrial transverse dimension, end-systolic eccentricity index and tricuspid annular plane systolic excursion improved significantly (58.8 ± 13.1 mm vs 53.7 ± 12.4 mm; 1.50 ± 0.27 vs 1.38 ± 0.23; 15.0 (13.0, 16.0) mm vs 15.8 (14.0, 17.4) mm, P < .005, respectively). One patient occurred sudden death after discharge during follow-up. CONCLUSIONS: Intravenous levosimendan can effectively improve severe RHF of PH patients in hospital and well tolerated.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Piridazinas/administração & dosagem , Receptores de Detecção de Cálcio/efeitos dos fármacos , Função Ventricular Direita , Doença Aguda , Adolescente , Adulto , Idoso , Cardiotônicos/administração & dosagem , China/epidemiologia , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Injeções Intravenosas , Pessoa de Meia-Idade , Estudos Prospectivos , Pressão Propulsora Pulmonar/fisiologia , Simendana , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-28762595

RESUMO

BACKGROUND: Previous studies suggest an increased inhibition of dorsal motor nucleus of the vagus (DMV) neurons following exposure to a perinatal high fat diet (PNHFD); the underlying neural mechanisms, however, remain unknown. This study assessed the effects of PNHFD on inhibitory synaptic inputs to DMV neurons and the vagally dependent control of gastric tone and motility. METHODS: Whole-cell patch clamp recordings were made from DMV neurons in thin brainstem slices from Sprague-Dawley rats fed either a control diet or HFD (14 or 60% kcal from fat, respectively) from embryonic day 13 onwards; gastric tone and motility were recorded in in vivo anesthetized rats. KEY RESULTS: The non-selective GABAA antagonist, BIC (10 µmol L-1 ), induced comparable inward currents in PNHFD and control DMV neurons, but a larger current in PNHFD neurons at higher concentrations (50 µmol L-1 ). Differences were not apparent in neuronal responses to the phasic GABAA antagonist, gabazine (GBZ), the extrasynaptic GABAA agonist, THIP, the GABA transport blocker, nipecotic acid, or the gliotoxin, fluoroacetate, suggesting that PNHFD altered inhibitory transmission but not GABAA receptor density or function, GABA uptake or glial modulation of synaptic strength. Similarly, the increase in gastric motility and tone following brainstem microinjection of low doses of BIC (1-10 pmoles) and GBZ (0.01-0.1 pmoles) were unchanged in PNHFD rats while higher doses of BIC (25 pmoles) induced a significantly larger increase in gastric tone compared to control. CONCLUSIONS AND INFERENCES: These studies suggest that exposure to PNHFD increases the tonic inhibition of DMV neurons, possibly contributing to dysregulated vagal control of gastric functions.


Assuntos
Tronco Encefálico/fisiologia , Dieta Hiperlipídica , Motilidade Gastrointestinal , Inibição Neural , Neurônios/fisiologia , Nervo Vago/fisiologia , Animais , Bicuculina/administração & dosagem , Agonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos , Isoxazóis/administração & dosagem , Masculino , Neurônios/efeitos dos fármacos , Piridazinas/administração & dosagem , Ratos Sprague-Dawley , Nervo Vago/efeitos dos fármacos
17.
Drugs R D ; 17(4): 631-643, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29103081

RESUMO

BACKGROUND: Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia. OBJECTIVES: Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs. METHODS: Healthy Japanese subjects (HJS) aged 20-55 years and subjects with stable schizophrenia (SSS) aged 18-55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period. RESULTS: TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined. CONCLUSIONS: Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. CLINICALTRIALS. GOV IDENTIFIER: NCT01879722.


Assuntos
Modelos Biológicos , Diester Fosfórico Hidrolases/metabolismo , Pirazóis , Piridazinas , Esquizofrenia/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Japão , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Esquizofrenia/metabolismo , Adulto Jovem
18.
J Hematol Oncol ; 10(1): 173, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-29132397

RESUMO

BACKGROUND: Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. METHODS: Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. RESULTS: Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. CONCLUSIONS: Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.


Assuntos
Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Animais , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Lipossarcoma , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Interferência de RNA
19.
BMC Anesthesiol ; 17(1): 128, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28915792

RESUMO

BACKGROUND: The effectiveness of a combination of a lipid emulsion with epinephrine in reversing local anesthetic-induced cardiac arrest has been confirmed. The combination of a lipid emulsion with levosimendan, was shown to be superior to administration of a lipid emulsion alone with regard to successful resuscitation. In this study, we compared the reversal effects of levosimendan, epinephrine, and a combination of the two agents in lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. METHODS: Fifty-four adult male Sprague-Dawley rats were subjected to bupivacaine (15 mg·kg-1) -induced asystole and were then randomly divided into 3 groups. A lipid emulsion was used as the basic treatment, and administration of drug combinations varied in each group as follows: (1) levosimendan combined with epinephrine (LiEL); (2) epinephrine (LiE); and (3) levosimendan (LiL). The resuscitation outcomes were recorded and included the rate of return of spontaneous circulation (ROSC) and survival at 40 min, time to first heartbeat, time to ROSC, and cumulative dose of epinephrine. We calculated the wet-to-dry ratio of the lung, blood gas values at 40 min and bupivacaine concentration of cardiac tissue and plasma. RESULTS: The rates of ROSC in LiEL and LiE groups were higher than LiL group (P < 0.001; LiEL vs LiL, P = 0.001; LiE vs LiL, P = 0.007). The survival rate in LiEL group was higher than LiE group (P = 0.003; LiEL vs LiE, P = 0.008; LiEL vs LiL, P = 0.001). The time to first heart beat in LiEL group was shorter than LiE, LiL groups. (P < 0.001; LiE vs LiEL, P = 0.001; LiL vs LiEL, P < 0.001). The time to ROSC in LiEL group was shorter than LiE, LiL groups (P < 0.001; LiEL vs LiE, P < 0.001; LiEL vs LiL, P < 0.001). The result was similar for the bupivacaine concentration of cardiac tissue and plasma (cardiac tissue: P = 0.002; plasma: P = 0.011). Furthermore, there were significant differences in the blood-gas values at 40 min, wet-to-dry lung weight ratio, and ratio of damaged alveoli among groups. The LiEL group had the best result for all parameters (P < 0.01, P = 0.008, P < 0.001, respectively). Additionally, significantly less epinephrine was used in the LiEL group (P < 0.001). CONCLUSIONS: Levosimendan combined with epinephrine may be superior to either drug alone for lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. The drug combination was associated with a higher survival rate as well as decreased epinephrine consumption and lung damage.


Assuntos
Bupivacaína/toxicidade , Reanimação Cardiopulmonar/métodos , Epinefrina/administração & dosagem , Emulsões Gordurosas Intravenosas/administração & dosagem , Parada Cardíaca/tratamento farmacológico , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Anestésicos Locais/toxicidade , Animais , Antiarrítmicos/administração & dosagem , Quimioterapia Combinada , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/fisiopatologia , Parada Cardíaca Induzida/métodos , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Simendana
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