Epothilones as Natural Compounds for Novel Anticancer Drugs Development.

Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium Sorangium cellulosum. This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.

Monitoramento do horizonte tecnológico: Medicamentos para tratamento de primeira linha do câncer de próstata metastático resistente à castração / Monitoring the technology horizon: Drugs for first-line treatment of metastatic castration-resistant prostate cancer

A DOENÇA: O câncer de próstata (CP) é uma doença heterogênea com diversos subtipos, que acomete a glândula próstata. A função dessa glândula é a produção do líquido prostático e do líquido seminal, que juntos são capazes de nutrir os espermatozoides e auxiliá-los na sua mobilidade. No adulto jovem a próstata possui o tamanho aproximado de uma ameixa, e pode de modo fisiológico aumentar de tamanho, de acordo com o envelhecimento. Na maioria dos casos o CP apresenta evolução silenciosa, podendo não apresentar sinais e sintomas em sua fase inicial. Entretanto, as manifestações clínicas mais comuns são: dificuldade de urinar, demora em iniciar ou finalizar o jato urinário, diminuição do jato urinário, necessidade de urinar mais vezes durante o dia ou a noite e presença de sangue na urina. Como esses sinais e sintomas são inespecíficos é necessário a avaliação médica para fins de diagnóstico diferencial. TRATAMENTOS SISTÊMICOS DE PRIMEIRA LINHA DISPONÍVEIS: As Diretrizes Diagnósticas e Terapêuticas (DDT) do adenocarcinoma de próstata, publicadas em 2016, estão em processo de atualização no momento. Para pacientes assintomáticos ou pouco sintomáticos é recomendado como tratamento de primeira linha a utilização de novos agentes inibidores do eixo de sinalização androgênica, preferencialmente, abiraterona ou enzalutamida (nível de evidência 1 e força de recomendação A). Para pacientes sintomáticos é recomendado como tratamento de primeira linha a quimioterapia com docetaxel e o radiofármaco Radium-223 (nível de evidência 1 e força de recomendação A). ESTRATÉGIA DE BUSCA: Os medicamentos em fase de desenvolvimento para o tratamento de primeira linha de pacientes com câncer de próstata metastático

Distribution of monocytes subpopulations in the peripheral blood from patients with Behçet's disease - Impact of disease status and colchicine use.

The innate immune response has a predominant role in Behçet's disease (BD) pathogenesis, but few studies have assessed monocytes in BD. This study aims to evaluate the profile of monocytes subsets in the peripheral blood of BD patients and healthy controls (HC). Monocytes subsets were identified as classical (CD14+CD16-), intermediate (CD14+CD16dim), and non-classical (CD14dimCD16high) subsets. Patients with BD presented a lower number of total monocytes (p = 0.020) and a lower number (p < 0.0001) of circulating classical monocytes than HC. In contrast, the number of intermediate monocytes was higher in BD patients than HC (p < 0.0001). In BD patients, no associations were observed with the severity of clinical manifestations or therapy. Colchicine was associated with a higher number of non-classical monocytes (p = 0.035). In conclusion, BD patients present an altered distribution of monocytes subsets with a reduction of classical and an increase of intermediate subsets.

Colchicine: A potential therapeutic tool against COVID-19. Experience of 5 patients.

COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

PURPOSE: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles.

OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). METHODS: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). RESULTS: The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue. CONCLUSION: The combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients.

Colchicine Treatment for Tracheobronchial Amyloidosis.

Tracheobronchial amyloidosis is an infrequent disease characterized by the deposition of proteinaceous material in the tracheobronchial tree. The disease generally has a high morbidity and variable mortality in the years following diagnosis. There is no consensus on the optimal treatment. We report a case of a 63-year-old woman who presented with a diffuse tracheobronchial amyloidosis associated with laryngeal involvement, which required a percutaneous tracheostomy due to high-grade subglottic stenosis, with no evidence of systemic amyloidosis. After treatment exclusively with colchicine, she had a complete resolution of the stenotic area, with a very good response from the tracheobronchial amyloidosis disease, with only minor yellow plaques persisting. The patient has remained asymptomatic in the next 4 years of follow-up, with no evidence of endoscopic progression. This is the first documented case of this kind of response of tracheobronchial amyloidosis to colchicine treatment alone. A review of the available literature is presented.

Effect of colchicine on myocardial injury induced by Trypanosoma cruzi in experimental Chagas disease.

BACKGROUND: The hallmark of Chagas disease (CD) is multifocal myocarditis and extensive fibrosis. We investigated the potential effect of colchicine on myocardial remodeling in experimental CD. METHODS AND RESULTS: One hundred Syrian hamsters were randomly divided into noninfected untreated control (CG), noninfected control treated with colchicine (COLG 0.4 mg kg(-1) d(-1) by gavage), infected (IG), and infected treated with colchicine (ICOLG, 0.4 mg kg(-1) d(-1)) groups. The interstitial collagen volume fraction (ICVF) was evaluated by videomorphometry with picrosirius red staining. The gelatinolytic activities of matrix metalloproteinase (MMP) 2 were examined with the use of zymography. Myocarditis was described according to the Dallas criteria. Statistical comparisons were performed with parametric analysis of variance and Tukey test. ICVF (%) accumulation was attenuated in infected colchicine-treated animals in the left (CG 0.81 ± 0.13, COLG 0.85 ± 0.13, IG: 1.35 ± 0.31,* ICOLG 1.06 ± 0.19; *P < .05 compared with ICOLG) and right ventricles (CG 1.4 ± 0.36, COLG 1.26 ± 0.14, IG 1.97 ± 0.058,* ICOLG: 1.52 ± 0.23; *P < .05 compared with ICOLG). A significant increase in MMP-2 enzymatic activity (UA) was observed in ICOLG (17,432.8*) compared with GC (3731.6), COLG (2,792.6), and IG (4,286.3; *P < .001). In IG, 66% of animals had myocarditis compared with only 49% in ICOLG. CONCLUSIONS: Colchicine had a protective effect on myocardium, indicated by decreased interstitial myocardial fibrosis, increased intensity of MMP-2, and attenuated myocardial inflammation.

Colchicine is a safe drug in children with familial Mediterranean fever.

OBJECTIVE: To identify any adverse effects of colchicine in a pediatric patients with familial Mediterranean fever (FMF). STUDY DESIGN: Clinical presentation, Mediterranean fever gene genotype, disease duration, colchicine dose, laboratory tests, and reported adverse effects in children with FMF were analyzed. RESULTS: Of the 153 patients with FMF, 22 (14.4%) developed diarrhea during a follow-up of 4 years; the colchicine dose was reduced to control this symptom in only 4 patients. In 18 (11.8%) patients, a mild transitory increase of transaminases (45-158 IU/L) was found during a follow-up of 1 year. Blood cell counts and kidney function tests were normal in all patients. No correlation was found between the adverse effects and patient's age, disease onset, treatment duration, or any of the clinical characteristics of the disease. CONCLUSION: Colchicine is a safe drug in the treatment of children with FMF, even in infancy. The only significant adverse effects are diarrhea (in a small number of patients), which can be controlled by a decrease in the colchicine dose and transitory elevation of transaminases.

Emerging drugs for coronary restenosis: the role of systemic oral agents the in stent era.

Introduction of drug eluting stents (DES) during percutaneous coronary interventions significantly reduces the rate of angiographic restenosis, target lesion and vessel revascularization. In spite of these benefits, other clinical hard end points such as death or myocardial infarction were not reduced and, furthermore, new concerns associated with the presence of late and very late stent thrombosis have been raised. The requirement of long-term dual antiplatelet therapy is another limitation associated with DES. Conversely, in this decade, other options to DES have been simultaneously discussed in observational and randomized studies. Several registries and randomized trials using the systemic approach with anti-inflammatory, immunosuppressive or antiplatelet therapies have been identified and discussed in this manuscript. In spite of all randomized studies with oral therapies in the bare metal stent (BMS) era demonstrating positive reductions in coronary restenosis, this practice has not been introduced clinically. Furthermore, a recent randomized trial comparing oral sirolimus plus BMS versus DES demonstrated that the first approach was cost saving and of comparable efficacy to DES. Conclusive evidence of high incidence of late and very late stent thrombosis with DES, together with clinical limitations for its widespread use, has opened up a large opportunity to search for alternative therapies in coronary restenosis prevention.

Urticaria unresponsive to antihistaminic treatment: an open study of therapeutic options based on histopathologic features.

BACKGROUND: The non- or low-sedating H1 receptor antagonists represent the basic therapy for urticaria. OBJECTIVE: To test an alternative approach to patients unresponsive to conventional treatment. MATERIALS AND METHODS: A total of 22 patients with chronic urticaria unresponsive to conventional antihistamine treatment were enrolled for this study. They had uncontrolled urticaria even using multiple combinations of antihistamines on maximum doses and corticosteroids in short cycles (prednisone 20-40 mg, per os once a day, 3-7 days per month). Cutaneous biopsies of the urticaria lesions were taken. These findings were classified as: (I) a mixture of perivascular dermal inflammatory infiltrate composed of lymphocytes, monocytes and neutrophils and/or eosinophils; (II) inflammatory infiltrate composed chiefly of neutrophils; and (III) inflammatory infiltrate composed mainly of eosinophils. According to histology, the patients were submitted to one of the following therapeutic schemes: class A - antihistamine treatment plus dapsone; class B - colchicine or dapsone; class C - montelukast. RESULTS: Four patients in class A, 08 in class B and seven in class C displayed complete control of urticaria after 12 weeks of treatment; one patient in class B and two in class C did not respond to treatment. Two years after discontinuation, 16 patients are still free of urticaria. CONCLUSIONS: This study suggests an alternative approach for treating unresponsive chronic urticaria.

[Colchicine: rationale for its use in liver disease]. / Colchicina. Fundamentos para su uso en enfermedades hepáticas.

Colchicine is a substance derived from the Colchicum Autumnale plant, its pharmacological uses have been demonstrated over the years. Initially used for the treatment of acute gout, it has been utilized for a wide variety of diseases, including mediterranean familial fever, alcoholic, posthepatitic and primary biliary liver cirrhosis. We have demonstrated in different studies that colchicine reduces markedly mortality rates in cirrhotics and the levels of interleukin-1 in patients with primary biliary cirrhosis.