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1.
Medicine (Baltimore) ; 100(4): e24463, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530256

RESUMEN

INTRODUCTION: Standardized systemic treatment options are lacking for carcinoma ex pleomorphic adenoma, which is a rare and aggressive tumor primarily found in salivary glands.Here we report the case of a 63-year-old male with carcinoma ex pleomorphic adenoma of the left parotid and parapharyngeal space harboring a neurotrophic receptor tyrosine kinase (NTRK) 2 fusion who was treated with a small molecule inhibitor that targets the tropomyosin receptor kinase (TRK) proteins. To the best of our knowledge, no similar case has been described in the literature so far. PATIENT CONCERNS: After multiple surgical resections and radiotherapy for localized cancer disease over several years, our patient again developed an increasing swelling and pain around the left ear and numbness of the left half of the face. DIAGNOSIS: Magnetic resonance imaging and positron emission tomography/computed tomography scans showed tumor recurrence in the left parotid, below the left ear, and in the parapharyngeal space, as well as metastases of the lungs and cervical lymph nodes. As data on the efficacy of systemic therapies for inoperable carcinoma ex pleomorphic adenoma are scarce, we performed a next-generation sequencing that revealed the presence of a hitherto unknown NTRK2 fusion. INTERVENTIONS: Treatment with the TRK inhibitor larotrectinib was initiated, which induced rapid symptom improvement. However, part of the tumor had to be removed shortly afterwards due to local progression. Molecular testing did not demonstrate any alterations accounting for resistance to larotrectinib, with maintenance of the NTRK2 fusion. OUTCOMES: Three months later, imaging confirmed mixed response. While the reason for this remains unknown, the patient is in good condition and continues to receive larotrectinib. CONCLUSION: It remains unclear why our patient showed mixed response to larotrectinib and further studies are needed to explore other possible mechanisms of resistance.


Asunto(s)
Adenoma Pleomórfico/tratamiento farmacológico , Neoplasias de la Parótida/tratamiento farmacológico , Neoplasias Faríngeas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/cirugía , Resistencia a Antineoplásicos , Humanos , Masculino , Glicoproteínas de Membrana , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Parótida/genética , Neoplasias de la Parótida/cirugía , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patología , Receptor trkB
2.
Khirurgiia (Mosk) ; (2): 67-72, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33570357

RESUMEN

OBJECTIVE: To compare the results of conservative and endovascular treatment of deep vein thrombosis followed by acute severe venous insufficiency. MATERIAL AND METHODS: Two statistically valid groups of patients with deep vein thrombosis and acute severe venous insufficiency were compared. Warfarin was administered in the first group, endovascular methods - in the second group (n=30). At the first step, we performed catheter-guided thrombolysis, then transcutaneous mechanical thrombectomy and venous stent deployment. Anticoagulation was achieved with Apixaban. Hemorrhagic complications were monitored during the treatment. One-year results were assessed considering lumen patency restoration and severity of venous congestion with Villalty score. RESULTS: In the first group, each third patient had hemorrhagic complications that required cessation of anticoagulant therapy in 1.3% of patients. In the second group, hemorrhagic events occurred in 10% of patients and were managed by lowering Apixaban dosage. Complete restoration of lumen patency was detected in 23.3% in the first group and 93.3% in the second group. Partial restoration developed in 63.3% and 6.7%, occlusion in 13.3% and 0%, respectively. Only 23.3% of patients in the first group had no clinical evidence of venous congestion. Mild congestion was found in 20%, severe - in 56.7% of cases. In the second group, 6.7% of patients had minimal venous congestion.


Asunto(s)
Anticoagulantes , Tratamiento Conservador , Procedimientos Endovasculares , Insuficiencia Venosa , Trombosis de la Vena , Enfermedad Aguda , Anticoagulantes/efectos adversos , Implantación de Prótesis Vascular , Tratamiento Conservador/métodos , Procedimientos Endovasculares/métodos , Humanos , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Stents , Trombectomía , Terapia Trombolítica/métodos , Resultado del Tratamiento , Grado de Desobstrucción Vascular/efectos de los fármacos , Insuficiencia Venosa/tratamiento farmacológico , Insuficiencia Venosa/etiología , Insuficiencia Venosa/cirugía , Trombosis de la Vena/complicaciones , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/cirugía , Warfarina/uso terapéutico
3.
Cochrane Database Syst Rev ; 1: CD007654, 2021 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-33454957

RESUMEN

BACKGROUND: This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES: Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. SELECTION CRITERIA: Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. MAIN RESULTS: This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.


Asunto(s)
Fármacos Antiobesidad/efectos adversos , Depresores del Apetito/efectos adversos , Hipertensión/tratamiento farmacológico , Adulto , Fármacos Antiobesidad/uso terapéutico , Depresores del Apetito/uso terapéutico , Sesgo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bupropión/efectos adversos , Bupropión/uso terapéutico , Dieta Reductora , Combinación de Medicamentos , Femenino , Fructosa/efectos adversos , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Humanos , Hipertensión/mortalidad , Lactonas/efectos adversos , Lactonas/uso terapéutico , Masculino , Persona de Mediana Edad , Naltrexona/efectos adversos , Naltrexona/uso terapéutico , Orlistat/efectos adversos , Orlistat/uso terapéutico , Fentermina/efectos adversos , Fentermina/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Retirada de Medicamento por Seguridad , Tiempo , Topiramato/efectos adversos , Topiramato/uso terapéutico
4.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33440983

RESUMEN

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Asunto(s)
Antivirales/uso terapéutico , /terapia , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Amidas/farmacología , Amidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Cloroquina/farmacología , Cloroquina/uso terapéutico , Combinación de Medicamentos , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Inmunización Pasiva , Indoles/farmacología , Indoles/uso terapéutico , Interferones/farmacología , Interferones/uso terapéutico , Ivermectina/farmacología , Ivermectina/uso terapéutico , Lopinavir/farmacología , Lopinavir/uso terapéutico , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Purinas/farmacología , Purinas/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ribavirina/farmacología , Ribavirina/uso terapéutico , Ritonavir/farmacología , Ritonavir/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Tiazoles/farmacología , Tiazoles/uso terapéutico
6.
Theranostics ; 11(1): 316-329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391477

RESUMEN

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Asunto(s)
Antiinflamatorios/uso terapéutico , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Inmunosupresores/uso terapéutico , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , /inmunología , Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Humanos , Inmunosupresores/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
7.
Xenobiotica ; 51(1): 5-14, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32662714

RESUMEN

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed to produce similar results in patients with ocular hypertension or open-angle glaucoma. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of MGV354 in an effort to understand potential differences in biotransformation pathways of MGV354 in rabbits, monkeys, and humans. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified in vitro and in vivo. In vitro hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of MGV354. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of MGV354 in clinical studies.


Asunto(s)
Antihipertensivos/metabolismo , Piperidinas/metabolismo , Pirazoles/metabolismo , Piridinas/metabolismo , Animales , Antihipertensivos/uso terapéutico , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Humanos , Presión Intraocular/efectos de los fármacos , Hipertensión Ocular/tratamiento farmacológico , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Conejos
10.
Cochrane Database Syst Rev ; 12: CD010966, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33331662

RESUMEN

BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators. OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data. MAIN RESULTS: We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Mutación , Adulto , Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Sesgo , Niño , Combinación de Medicamentos , Humanos , Indoles/uso terapéutico , Fenilbutiratos/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Calidad de Vida , Quinolinas/uso terapéutico , Quinolonas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto
11.
Zhonghua Nan Ke Xue ; 26(4): 364-368, 2020 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33351306

RESUMEN

Prostate cancer (PCa) is one of the most common tumors in male. Castration-resistant PCa (CRPC) refers to the prostate malignancy with a PSA increase or imaging progression after androgen-deprivation therapy (ADT), which is divided into metastatic CRPC (mCRPC) and non-metastatic CRPC (nmCRPC) based on the presence or absence of imaging metastasis. Two second-generation antiandrogens, enzuramide and abiraterone, were approved for the treatment of nmCRPC in 2018. A recently completed three-stage large-scale clinical ARAMIS trial shows that the new drug, darolutamide, compared with the placebo, could prolong the metastasis-free survival (MFS) of nmCRPC patients. Darolutamide is now an anti-androgen drug available for patients with nmCRPC. This review focuses on the clinical trial of darolutamide and comparison of its therapeutic effect with that of another two second-generation antiandrogens.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración , Pirazoles/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
12.
Rev Med Suisse ; 16(719): 2428-2431, 2020 Dec 16.
Artículo en Francés | MEDLINE | ID: mdl-33325660

RESUMEN

Venous thrombotic events frequently complicate major elective arthroplasties such as hip and knee replacements. The risk of proximal deep vein thrombosis and pulmonary embolism is estimated at 5 %. For decades, the use of low-dose heparins for up to 5 weeks post-surgery has helped to reduce the risk of thrombotic complications. In this narrative review, we describe the evidence supporting the use of direct oral anticoagulants (in Switzerland - rivaroxaban and apixaban), whose risk-benefit ratios appears superior to that of heparins, at a lower cost. Hybrid strategies combining a short-term anticoagulant followed by low-dose aspirin are also recommended for patients deemed at low thrombotic risk.


Asunto(s)
Anticoagulantes/uso terapéutico , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Heparina/uso terapéutico , Humanos , Embolia Pulmonar/etiología , Embolia Pulmonar/prevención & control , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Rivaroxabán/uso terapéutico
13.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-33317057

RESUMEN

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis , Neoplasias Pulmonares/metabolismo , Estrés Oxidativo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Colesterol/análogos & derivados , Colesterol/farmacología , Colesterol/uso terapéutico , Regulación hacia Abajo , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Pirazoles/farmacología , Pirazoles/uso terapéutico , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo
14.
Zhonghua Xue Ye Xue Za Zhi ; 41(11): 890-895, 2020 Nov 14.
Artículo en Chino | MEDLINE | ID: mdl-33333690

RESUMEN

Objective: To evaluate the safety and efficacy of eltrombopag combined with immunosuppressive therapy in patients with aplastic anemia (AA) in China. Methods: We investigated and analyzed the clinical data of AA patients from 14 hematological treatment centers who were treated with oral eltrombopag for at least 3 mon. Results: We enrolled 56 AA patients, including 19 treatment-naïve patients and 37 IST-refractory patients. The median administration period for eltrombopag was 7 (3-31) months, and the median maximum stable dosage was 75 mg/d (50-150 mg/d) . The 3-month hematological response (HR) rate was 60%, and the complete response (CR) rate was 30% in 10 SAA patients who were treated with first-line eltrombopag and standard IST (ATG+CsA) . Eight of 9 eltrombopag and CsA ± androgen first-line treated SAA patients responded (8/9, 89%) and 4 (44%) gave CR. The overall HR and CR rates were 79% and 52.6%, respectively, among these 19 patients by the end of the follow-up period. Of the 19 AA patients who were refractory to CsA ± androgen, 11 achieved HR (57.9%) at 3 mon, and the best HR rate was 44% in standard IST (ATG+CsA) refractory 18 patients after eltrombopag treatment. Fifty-one percent of the patients experienced mild or moderate adverse events, and gastrointestinal discomfort was the most common adverse effect reported by the study subjects. Conclusion: Adding Eltrombopag in first-line IST can accelerate the acquisition and improve the quality of hematological responses in AA patients. AA with relatively more residual hematopoietic cells may be well treated with eltrombopag and non-ATG IST. Eltrombopag can be used as salvage therapy for CsA±androgen refractory patients. Eltrombopag was generally safe and well tolerated by AA patients in China.


Asunto(s)
Anemia Aplásica , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Pirazoles/uso terapéutico , Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico , China , Ciclosporina , Humanos , Inmunosupresores , Encuestas y Cuestionarios , Resultado del Tratamiento
15.
J Pharmacol Sci ; 144(4): 229-236, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33070842

RESUMEN

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/complicaciones , Adenina/efectos adversos , Anemia/tratamiento farmacológico , Anemia/etiología , Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa , Pirazoles/uso terapéutico , Triazoles/uso terapéutico , Lesión Renal Aguda/metabolismo , Animales , Modelos Animales de Enfermedad , Eritropoyetina/metabolismo , Masculino , Ratones Endogámicos C57BL , Pirazoles/administración & dosificación , Pirazoles/farmacología , Triazoles/administración & dosificación , Triazoles/farmacología
16.
JAMA ; 324(15): 1522-1531, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33079154

RESUMEN

Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. Objective: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. Design, Setting, and Participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). Main Outcomes and Measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). Conclusions and Relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT03254485.


Asunto(s)
Tolerancia al Ejercicio/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Oxígeno/metabolismo , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Administración Oral , Anciano , Método Doble Ciego , Femenino , Guanilato Ciclasa/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hospitalización , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Pirazoles/farmacología , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Volumen Sistólico , Insuficiencia del Tratamiento , Prueba de Paso
17.
Drugs Today (Barc) ; 56(8): 531-539, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33025948

RESUMEN

Mantle cell lymphoma (MCL) has historically been an aggressive disease with poor long-term survival. In the last decade, Bruton tyrosine kinase (BTK) inhibition has emerged as a new treatment strategy for MCL, especially in the relapsed/refractory (r/r) setting. Zanubrutinib, a second-generation BTK inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for r/r MCL on the basis of combined overall response rate of 84% in a total of 118 patients from two multicenter clinical trials, BGB-3111-AU-003 and BGB-3111-206. Duration of response was 14-18 months. Although 57% of patients developed grade 3 and 4 adverse side effects including anemia, pneumonia and neutropenia, only 8% discontinued treatment suggesting zanubrutinib monotherapy was fairly well tolerated. As compared to first-generation ibrutinib, zanubrutinib has higher BTK selectivity which may result in fewer off-target effects and improved potential for combination with other targeted therapies. In addition to a confirmatory phase III trial, there are multiple ongoing studies evaluating zanubrutinib as part of two- and three-drug regimens in MCL and other B-cell malignancies. These current results and areas of further interest indicate an exciting future for zanubrutinib in the treatment of MCL.


Asunto(s)
Linfoma de Células del Manto/tratamiento farmacológico , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Humanos , Estudios Multicéntricos como Asunto , Inhibidores de Proteínas Quinasas/uso terapéutico , Estados Unidos
18.
Drugs Today (Barc) ; 56(9): 561-571, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33025950

RESUMEN

Avapritinib is a tyrosine kinase inhibitor (TKI) that has recently received Food and Drug Administration (FDA) approval for the treatment of metastatic or unresectable gastrointestinal stromal tumors harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Mutations in the activation loop of PDGFRA or KIT confer resistance to conventional TKIs due to structural changes in the receptor. Avapritinib was developed to selectively target these mutations, thereby offering a new treatment option for patients in whom imatinib, sunitinib, and regorafenib have failed. This review covers the basic science and preclinical studies that guided avapritinib's development, in addition to the data currently available from early clinical studies as well as those later-stage trials that led to its approval.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Triazinas/uso terapéutico , Ensayos Clínicos como Asunto , Tumores del Estroma Gastrointestinal/genética , Humanos , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Estados Unidos
20.
Eur Heart J ; 41(41): 4037-4046, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32984892

RESUMEN

AIMS: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. METHODS AND RESULTS: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. CONCLUSIONS: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.


Asunto(s)
Fibrilación Atrial/sangre , Betacoronavirus , Infecciones por Coronavirus/sangre , Peptidil-Dipeptidasa A/sangre , Neumonía Viral/sangre , Anciano , Antitrombinas/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Biomarcadores/sangre , Estudios de Cohortes , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Dabigatrán/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Factores de Riesgo , Accidente Cerebrovascular/prevención & control , Warfarina/uso terapéutico
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