Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.697
Filtrar
1.
BMC Vet Res ; 15(1): 237, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288807

RESUMO

BACKGROUND: Exercise testing in conjunction with measurement of cardiac biomarkers NT-proBNP and cTnI is a useful tool for monitoring the effect of treatment on cardiac patients. Administering Pimobendan in dogs with degenerative mitral valve disease (DMVD) and cardiomegaly results in delaying the onset of clinical symptoms and prolonging life. Its effect in dogs with DMVD without cardiomegaly has not been well examined. The aim of the current study was to investigate the effect of administering Pimobendan in dogs with DMVD without cardiomegaly using exercise testing in conjunction with measuring cardiac biomarkers in addition to echocardiography. Twenty-one dogs with asymptomatic DMVD without echocardiographic signs of cardiomegaly participated in a randomised, double-blinded trial. Dogs were divided into a Pimobendan-group (n = 11) and a placebo-group (n = 10) in a double-blinded study design and underwent a standardised submaximal exercise test (SSET). One dog in the Pimobendan-group was retrospectively removed from the study after being diagnosed with Leishmaniosis. Cardiac biomarkers NT-proBNP and cTnI were measured before and after exercise. Follow-up appointments were performed at days 90 and 180. RESULTS: Dogs in the Pimobendan-group had significantly lower post-exercise NT-proBNP-levels after being administered Pimobendan than at the beginning of the study. They also had lower pre- and post-exercise-NT-proBNP-levels than those dogs in the placebo-group. There was neither a significant difference regarding the measured cTnI levels nor an increase in cTnI between the groups at any time. CONCLUSIONS: Pimobendan lowers NT-proBNP in dogs with presymptomatic mitral valve disease without cardiomegaly before and after submaximal exercise. This indicates a reduction in cardiac wall stress. If dogs with asymptomatic DMVD without cardiomegaly benefit from treatment with Pimobendan (for example, through a longer survival time) warrants further investigation.


Assuntos
Doenças do Cão/sangue , Doenças do Cão/tratamento farmacológico , Teste de Esforço/veterinária , Doenças das Valvas Cardíacas/veterinária , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Piridazinas/uso terapêutico , Troponina I/sangue , Animais , Biomarcadores/sangue , Cães , Feminino , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/tratamento farmacológico , Masculino , Condicionamento Físico Animal/fisiologia , Piridazinas/farmacologia , Distribuição Aleatória , Estresse Fisiológico/efeitos dos fármacos , Resultado do Tratamento
2.
Medicine (Baltimore) ; 98(20): e15632, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096477

RESUMO

BACKGROUND: It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence. METHODS: PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test. RESULTS: Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death. CONCLUSIONS: This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.


Assuntos
Anti-Hipertensivos/uso terapêutico , Complexo de Eisenmenger/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Oxigênio/sangue , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Prostaglandinas/administração & dosagem , Prostaglandinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico
3.
Br J Anaesth ; 123(2): e194-e203, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30915991

RESUMO

BACKGROUND: This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABAA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control. METHODS: We performed a randomised placebo-controlled crossover study (NCT02238717) in 20 healthy subjects, using a battery of pain tasks (electrical, pressure, heat, cold and inflammatory pain, including a paradigm of conditioned pain modulation). Pharmacodynamic measurements were performed at baseline and up to 10 h after dose. RESULTS: A dose of 15 mg PF-06372865 increased pain tolerance thresholds (PTTs) for pressure pain at a ratio of 1.11 (90% confidence interval [CI]: 1.02, 1.22) compared with placebo. A dose of 65 mg PF-06372865 led to an increase in PTT for the cold pressor at a ratio of 1.17 (90% CI: 1.03, 1.32), and pressure pain task: 1.11 (90% CI: 1.01, 1.21). Pregabalin showed an increase in PTT for pressure pain at a ratio of 1.15 (95% CI: 1.06, 1.26) and cold pressor task: 1.31 (90% CI: 1.16, 1.48). CONCLUSION: We conclude that PF-06372865 has analgesic potential at doses that do not induce significant sedation or other intolerable adverse events limiting its clinical use. In addition, the present study established the potential role for this battery of pain tasks as a tool in the development of analgesics with a novel mechanism of action, for the treatment of various pain states including neuropathic pain and to establish proof-of-concept. CLINICAL TRIALS REGISTRATION: NCT0223871.


Assuntos
Analgésicos/farmacologia , Imidazóis/farmacologia , Dor/tratamento farmacológico , Piridazinas/farmacologia , Adulto , Analgésicos/uso terapêutico , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imidazóis/uso terapêutico , Masculino , Piridazinas/uso terapêutico
4.
Life Sci ; 222: 133-139, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844374

RESUMO

BACKGROUND: Cigarette smoke is exogenous modifiable factors to changes the neurovascular complication. The chronic exposure of cigarette smoke enhances neurocognitive dysfunction. AIMS: The present study is focused on evaluating the role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke-induced cognitive impairment in Danio rerio. MAIN METHODS: The cognitive dysfunction was developed by cigarette smoke exposure (CSE; 10 min in 25 ml of CSE per day) for five days. The selective endothelin-A receptor antagonist i.e., ambrisentan (2.5 to 5 mg/kg; i.p. for five consecutive days) was used for testing of CSE induced cognitive dysfunction. In addition, treatment of reference drug i.e., donepezil (10 mg/kg; i.p. for five consecutive days) was used for this cognitive function study. The cognitive functions were assessed by light and dark chamber; color recognition; partition preference; horizontal compartment; and T-Maze tests. Further, the CSE induced biomarkers changes of the zebrafish brain samples were estimated. KEY FINDINGS: The treatment of ambrisentan showed a potential ameliorative effect against the CSE induced cognitive functions along with attenuation of biochemical changes. The results are comparable to donepezil-treated groups. SIGNIFICANCE: Therefore, ambrisentan can be considered for the attenuation of CSE induced impairment neurocognitive functions due to its reduction of free radical scavenging and neuroinflammatory actions as well as regulation of cholinergic neurotransmitter functions.


Assuntos
Fumar Cigarros/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Fumar Cigarros/tendências , Disfunção Cognitiva/psicologia , Antagonistas do Receptor de Endotelina A/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Fumaça/efeitos adversos , Peixe-Zebra
5.
Hematol Oncol ; 37(3): 296-302, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30892724

RESUMO

Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.


Assuntos
Oclusão Coronária/induzido quimicamente , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piridazinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Cardiologia/métodos , Oclusão Coronária/complicações , Sistemas de Apoio a Decisões Clínicas , Feminino , Humanos , Hipertensão/induzido quimicamente , Imidazóis/uso terapêutico , Incidência , Itália/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Piridazinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
6.
Rinsho Ketsueki ; 60(1): 33-38, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30726822

RESUMO

Our patient was diagnosed with chronic myeloid leukemia (CML) in chronic phase (CP) when he was 40 years old. Although dasatinib (DAS) was prescribed during his clinical course, he was poorly compliant with the treatment. In November 20XX, at 65 years of age, he visited our hospital with leukocytosis. He was diagnosed with CML in CP and recommenced DAS at 50 mg/day, achieving a complete hematological response after 2 months. However, DAS was increased to 100 mg/day because only minimum cytogenetic response was evident even after 9 months, but CML progressed to the accelerated phase after 18 months. The ABL kinase domain mutations T315I and F317L were detected. Ponatinib (PON) was not yet approved, and he declined allogeneic stem cell transplantation therapy. He commenced interferon-α (IFN-α) in addition to DAS, and the F317L mutation (only) disappeared after 7 months; the patient achieved a major cytogenetic response. In January 20XX+4, he commenced PON monotherapy (the drug was approved by this time) and achieved a major molecular response after 8 months. The T315I mutation disappeared during PON therapy. Although IFN-α is rarely used in the treatment of CML, this case suggests that IFN-α should be re-considered in patients with CML who exhibit tyrosine kinase inhibitor resistance.


Assuntos
Imidazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Oncogênicas v-abl/genética , Piridazinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
7.
Int J Antimicrob Agents ; 53(4): 515-519, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769200

RESUMO

This study investigated the prevalence of doravirine (DOR) resistance mutations in non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced patients. DOR resistance was assessed in samples from NNRTI-experienced patients who underwent genotypic testing for virological failure from the Antiretroviral Response Cohort Analysis (ARCA) database. Intermediate DOR resistance was defined as detection of any of V106A/M, Y188C/H, V108I, and K103N+P225H. High-level DOR resistance was defined as detection of any of Y188L, M230L, G190E, V106A/M+F227L, and V106A/M+L234I. Overall, 6893 patients were included in the study: 64.2% had experienced efavirenz (EFV), 54.4% nevirapine (NVP), 6.8% etravirine (ETR), 7.7% rilpivirine (RPV) and 0.7% delavirdine. Among NNRTI-experienced patients, 12.7% and 6.1% of subjects had intermediate and high-level DOR resistance, respectively. The most common DOR resistance mutation was Y188L. In multivariable analysis, previous EFV use (OR = 1.52, 95% CI 1.15-2.02) and ETR use (OR = 1.91, 95% CI 1.34-2.73) were associated with detection of high-level DOR resistance, whilst RPV use was associated with a lower probability of high-level DOR resistance (OR = 0.39, 95% CI 0.22-0.71). Moreover, EFV use (OR = 1.76, 95% CI 1.19-2.58) and ETR use (OR = 1.72, 95% CI 1.10-2.68) were associated with detection of the Y188L mutation, whereas RPV use was not (OR = 0.16, 95% CI 0.05-0.50). In Italy, DOR resistance is uncommon among NNRTI-experienced patients, confirming a distinguishing resistance pattern within NNRTIs. However, previous EFV and ETR experience poses a higher risk of DOR resistance. These results support the use of DOR in NNRTI-experienced patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Triazóis/uso terapêutico , Adulto , Benzoxazinas/uso terapêutico , Estudos Transversais , Delavirdina/uso terapêutico , Feminino , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Masculino , Nevirapina/uso terapêutico , Piridazinas/uso terapêutico , Rilpivirina/uso terapêutico , Resultado do Tratamento
8.
Acta Haematol ; 141(2): 107-110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695783

RESUMO

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/metabolismo , Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Terapia Baseada em Transplante de Células e Tecidos , Quimioterapia Combinada , Humanos , Masculino , Cromossomo Filadélfia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Recidiva
9.
J Clin Psychopharmacol ; 39(1): 20-27, 2019 Jan/Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30531477

RESUMO

BACKGROUND: Generalized anxiety disorder (GAD) is a common psychiatric disorder, but many patients experience only partial relief of symptoms with existing therapies. Benzodiazepines are effective in many cases but are limited by a number of significant adverse effects. PF-06372865 is a subtype-selective gamma-aminobutyric acid A (GABAA)-positive allosteric modulator lacking in functional activity at alpha 1-containing receptors that are believed to mediate many of these adverse effects. METHODS: PF-06372865 was evaluated as an adjunct to current GAD treatment in a double-blind, placebo-controlled, sequential parallel comparison study in patients with GAD who showed an incomplete response to current standard-of-care pharmacotherapy. A total of 90 subjects (of the planned 384) were randomized into the study before the decision to terminate the study. Two doses of PF-06372865 (2.5 mg twice daily and 7.5 mg twice daily) were compared with placebo. RESULTS: Neither dose of PF-06372865 differentiated from placebo on week 4 Hamilton Anxiety Inventory total (primary end point) or on the Sheehan Disability Scale total score (secondary end point). Adverse events including dizziness, headache, and somnolence were observed, and the 7.5 mg dose demonstrated some impairment on the Digit Symbol Substitution test and the Epworth Sleepiness Scale relative to placebo and the 2.5 mg dose. CONCLUSIONS: Factors contributing to the negative results include the limited sample size and failure to explore a broader range of doses.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Imidazóis/uso terapêutico , Piridazinas/uso terapêutico , Adolescente , Adulto , Ansiolíticos/efeitos adversos , Ansiolíticos/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/sangue , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Piridazinas/efeitos adversos , Piridazinas/sangue , Padrão de Cuidado , Resultado do Tratamento , Suspensão de Tratamento , Adulto Jovem
10.
BMC Cancer ; 18(1): 1229, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30526517

RESUMO

BACKGROUND: Atypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (µ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib. CASE PRESENTATION: Here we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT). CONCLUSION: This case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.


Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação/genética , Piridazinas/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva
11.
Can Respir J ; 2018: 1015239, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581511

RESUMO

Objectives: Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication. Methods: Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments. Results: A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain. Conclusions: Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Anti-Hipertensivos/economia , Anti-Hipertensivos/uso terapêutico , Bosentana/economia , Análise Custo-Benefício , Antagonistas dos Receptores de Endotelina/economia , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Humanos , Fenilpropionatos/economia , Fenilpropionatos/uso terapêutico , Piridazinas/economia , Piridazinas/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/economia , Vasodilatadores/uso terapêutico
12.
Zhonghua Nei Ke Za Zhi ; 57(6): 423-428, 2018 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-29925127

RESUMO

Objective: To investigate the effect of levosimendan on cardiac function and prognosis in elderly patients with septic myocardial contractility impairment. Methods: A prospective, randomized, controlled study was conducted. The elderly patients with septic myocardial contractility impairment who were admitted to Intensive Care Unit in Zhejiang Hospital were consecutively enrolled from January 2017 to September 2017. The key inclusive criterion was left ventricular ejection fraction (LVEF) ≤50% after fluid resuscitation. A total of 30 patients were randomly assigned to levosimendan group (n=15) and dobutamine group (n=15). Based onconventional treatment, intravenous dobutamine (5 µg per kilogram of body weight per minute) or levosimendan (0.2 µg per kilogram of body weight per minute)were continuously administrated for 24 hours in two groups. At 0 h,24 h,48 h, 72 h after injection, the following parameters or values were recorded including serum lactic acid (Lac), and echocardiographic parameters such as LVEF, stroke volume (SV). The time of mechanical ventilation, length of stay in ICU and 28-day mortality were compared in two groups. Results: Compared with dobutamine group, blood Lac at 24 h [(1.97±1.10)mmol/L vs. (2.73±2.06) mmol/L, P=0.002] decreased significantlyin levosimendan group. LVEF and SV were significantly higher in levosimendan group at 24 h [LVEF:(47.93±5.01)% vs.(45.60±5.47)%, P=0.004;SV:(47.73±14.01) ml vs. (44.80±16.89) ml, P=0.035;respectively], 48 h [LVEF:(51.07±5.05)% vs.(46.73±6.34)%, P=0.004;SV: (49.87±14.15) ml vs. (45.07±16.94) ml, P=0.005;respectively] and 72 h [LVEF:(53.20±5.92)% vs. (47.70±6.71)%, P=0.002;SV:(51.27±14.98) ml vs. (45.73±17.34) ml, P=0.010]. The time of mechanical ventilation, length of stay in ICU and 28-day mortality were comparable between two groups (P>0.05). Conclusions: Levosimendan improves cardiac systolic function and tissue perfusion in elderly patients with septic myocardial contractility impairment. However, cardiac diastolic function, liver and kidney function are not further improved by levosimendan compare with dubutamine. Time of mechanical ventilation, length of stay in ICU and 28-day mortality in two groups are similar.


Assuntos
Hidratação , Hidrazonas/farmacologia , Miocárdio/patologia , Piridazinas/farmacologia , Choque Séptico/tratamento farmacológico , Idoso , Biomarcadores/sangue , Ecocardiografia , Insuficiência Cardíaca , Humanos , Hidrazonas/uso terapêutico , Unidades de Terapia Intensiva , Ácido Láctico/sangue , Prognóstico , Estudos Prospectivos , Piridazinas/uso terapêutico , Respiração Artificial , Choque Séptico/sangue , Choque Séptico/fisiopatologia , Simendana , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
13.
Drug Des Devel Ther ; 12: 1777-1783, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29950812

RESUMO

Despite the progress in the management of cerebral arterial aneurysms, subarachnoid hemorrhage (SAH) remains the major cause of neurological disability. While SAH-related deaths usually occur as a result of brain impairment due to hemorrhage, permanent neurological deficits are caused by cerebral ischemia due to edema and spasm of cerebral arteries. Additionally, ~20%-30% of patients with SAH develop secondary cardiomyopathy; this phenomenon is known as neurogenic stress cardiomyopathy (NSC), which is associated with increased mortality and poor long-term prognosis. Levosimendan is a new inotropic drug that causes calcium sensitization of troponin C, thus increasing contraction force of myofilaments. The drug also causes opening of ATP-dependent potassium channels in vascular smooth muscles, which results in dilatation of veins and arteries, including cerebral arteries. To date, there have been several reports of levosimendan application in patients with SAH and neurogenic stress cardiomyopathy, and the effect of the drug on vasospasm has been previously advocated. This paper presents a case report of a 57-year-old patient with massive SAH, where levosimendan was used for reducing vasospasm.


Assuntos
Artérias Cerebrais/efeitos dos fármacos , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Angiografia Cerebral/métodos , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/fisiopatologia , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Hidrazonas/efeitos adversos , Pessoa de Meia-Idade , Piridazinas/efeitos adversos , Simendana , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/fisiopatologia , Resultado do Tratamento , Vasodilatadores/efeitos adversos , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/fisiopatologia
14.
Biomed Res Int ; 2018: 7563083, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854789

RESUMO

Background: Recent studies suggest that levosimendan does not provide mortality benefit in patients with low cardiac output syndrome undergoing cardiac surgery. These results conflict with previous findings. The aim of the current study is to assess whether levosimendan reduces postoperative mortality in patients with impaired left ventricular function (mean EF ≤ 40%) undergoing cardiac surgery. Methods: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library Database through November 20, 2017. Inclusion criteria were random allocation to treatment with at least one group receiving levosimendan and another group receiving placebo or other treatments and cardiac surgery patients with a left ventricular ejection fraction of 40% or less. The primary endpoint was postoperative mortality. Secondary outcomes were cardiac index, pulmonary capillary wedge pressure (PCWP), length of intensive care unit (ICU) stay, postoperative atrial fibrillation, and postoperative renal replacement therapy. We performed trial sequential analysis (TSA) to evaluate the reliability of the primary endpoint. Results: Data from 2,152 patients in 15 randomized clinical trials were analyzed. Pooled results demonstrated a reduction in postoperative mortality in the levosimendan group [RR = 0.53, 95% CI (0.38-0.73), I2 = 0]. However, the result of TSA showed that the conclusion may be a false positive. Secondary outcomes demonstrated that PCWP, postoperative renal replacement therapy, and length of ICU stay were significantly reduced. Cardiac index was greater in the levosimendan group. No difference was found in the rate of postoperative atrial fibrillation. Conclusions: Levosimendan reduces the rate of death and other adverse outcomes in patients with low ejection fraction who were undergoing cardiac surgery, but results remain inconclusive. More large-volume randomized clinical trials (RCTs) are warranted.


Assuntos
Cardiotônicos/uso terapêutico , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Baixo Débito Cardíaco/tratamento farmacológico , Baixo Débito Cardíaco/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Humanos , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia de Substituição Renal , Simendana , Disfunção Ventricular Esquerda/cirurgia
15.
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
16.
Basic Clin Pharmacol Toxicol ; 123(2): 103-113, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29719121

RESUMO

The approval of macitentan has increased the number of pharmacological treatments of pulmonary arterial hypertension (PAH). Here, we review the effect on PAH of macitentan compared to other endothelin receptor antagonists. Drugs targeting the endothelin (ET) pathway include the selective ETA receptor antagonist ambrisentan, the ETA /ETB receptor antagonists, bosentan and macitentan, which were recently approved for PAH treatment. Macitentan exhibits higher antagonistic potency than bosentan and ambrisentan in pulmonary smooth muscle cells. Compared to ambrisentan and bosentan, macitentan has a longer duration of action, reflected by the longer half-life, as well as pharmacodynamics attributed to its active metabolite, ACT-132577. The efficacy of macitentan on PAH was investigated in the phase III SERAPHIN trial (NCT00660179). Macitentan significantly reduced morbidity and mortality. It improved the 6-min. walk distance (6MWD) among PAH patients. In the AMB-320/321-E (NCT00578786) study, ambrisentan improved exercise capacity. In the EARLY study (NCT00091715), bosentan showed improvements in 6MWD which were not statistically significant. Bosentan had an effect on PAH in patients with Eisenmenger syndrome (ES) in the BREATHE-5 study (NCT00367770), while macitentan did not improve 6MWD in these patients, but there are differences regarding study size and functional class, and that 30% of the patients treated with macitentan were already in treatment with a phosphodiesterase type 5 inhibitor. Macitentan revealed a lower risk of developing peripheral oedema and hepatotoxicity in the SERAPHIN study. In summary, macitentan has an efficiency comparable to bosentan and ambrisentan in the treatment of PAH. Patients treated with macitentan exhibited less adverse effects compared to bosentan and ambrisentan. In patients with PAH associated with ES, the trials with bosentan and macitentan do not seem comparable, and it needs to be clarified whether these drugs are effective when administered as part of a combination treatment in this condition.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Bosentana , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada/métodos , Antagonistas dos Receptores de Endotelina/farmacologia , Meia-Vida , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fenilpropionatos/farmacologia , Fenilpropionatos/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Resultado do Tratamento , Teste de Caminhada
17.
Bioorg Med Chem ; 26(12): 3308-3320, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29739714

RESUMO

We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33 nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/-p53-/- mouse medulloblastoma allograft model also indicated encouraging results.


Assuntos
Antineoplásicos/síntese química , Proteínas Hedgehog/metabolismo , Piridazinas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Modelos Animais de Doenças , Desenho de Drogas , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Simulação de Acoplamento Molecular , Piridazinas/metabolismo , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/química , Receptor Smoothened/metabolismo , Relação Estrutura-Atividade , Transplante Homólogo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
18.
Orv Hetil ; 159(22): 870-877, 2018 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-29806474

RESUMO

Low output syndrome significantly increases morbidity and mortality of cardiac surgery and lengthens the durations of intensive care unit and hospital stays. Its treatment by catecholamines can lead to undesirable systemic and cardiac complications. Levosimendan is a calcium sensitiser and adenosine triphosphate (ATP)-sensitive potassium channel (IK,ATP) opener agent. Due to these effects, it improves myocardium performance, does not influence adversely the balance between O2 supply and demand, and possesses cardioprotective and organ protective properties as well. Based on the scientific literature and experts' opinions, a European recommendation was published on the perioperative use of levosimendan in cardiac surgery in 2015. Along this line, and also taking into consideration cardiac surgeon, anaesthesiologist and cardiologist representatives of the seven Hungarian heart centres and the children heart centre, the Hungarian recommendation has been formulated that is based on two pillars: literature evidence and Hungarian expert opinions. The reviewed fields are: coronary and valvular surgery, assist device implantation, heart transplantation both in adult and pediatric cardiologic practice. Orv Hetil. 2018; 159(22): 870-877.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Cardiotônicos/uso terapêutico , Hidrazonas/uso terapêutico , Cuidados Pré-Operatórios/métodos , Piridazinas/uso terapêutico , Doenças Cardiovasculares/cirurgia , Humanos , Hungria , Simendana
19.
Ann Hematol ; 97(9): 1577-1580, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29675611

RESUMO

Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.


Assuntos
Imidazóis/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/epidemiologia , Padrões de Prática Médica/estatística & dados numéricos , Piridazinas/uso terapêutico , Adulto , Idoso , Quimioterapia Adjuvante , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
J Vet Intern Med ; 32(3): 944-950, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29635788

RESUMO

BACKGROUND: Dogs with advanced heart failure are a clinical challenge for veterinarians but there are no studies reporting clinical features and outcome of this population. HYPOTHESIS/OBJECTIVES: To describe clinical findings and outcome of dogs with advanced heart failure caused by degenerative mitral valve disease (DMVD). ANIMALS: Fifty-four dogs with advanced heart failure because of DMVD. METHODS: For study purposes, advanced heart failure was defined as recurrence of congestive heart failure signs despite receiving the initially prescribed dose of pimobendan, angiotensin-converting-enzyme inhibitor (ACEI), and furosemide >4 mg/kg/day. Data were collected for the time of diagnosis of Stage C heart failure and time of diagnosis of advanced heart failure. Date of death was recorded. RESULTS: At the diagnosis of advanced heart failure, doses of pimobendan (n = 30), furosemide (n = 28), ACEI (n = 13), and spironolactone (n = 4) were increased, with ≥1 new medications added in most dogs. After initial diagnosis of advanced heart failure, 38 (70%) dogs had additional medications adjustments (median = 2 [range, 0-27]), with the final total medication number ranging from 2-10 (median = 5). Median survival time after diagnosis of advanced heart failure was 281 days (range, 3-885 days). Dogs receiving a furosemide dose >6.70 mg/kg/day had significantly longer median survival times (402 days [range, 3-885 days] versus 129 days [range 9-853 days]; P = .017). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with advanced heart failure can have relatively long survival times. Higher furosemide dose and non-hospitalization were associated with longer survival.


Assuntos
Doenças do Cão/mortalidade , Insuficiência Cardíaca/veterinária , Animais , Cardiotônicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Furosemida/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Masculino , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/veterinária , Piridazinas/uso terapêutico , Espironolactona/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA