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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
2.
Molecules ; 24(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438508

RESUMO

Oral mucositis is one of the most frequent complications after chemotherapy or radiotherapy or a combination of both. There is no standard therapy for its prevention or treatment. Considering that some bee products have been found to be of value in this situation, we decided to analyze the scientific literature on the subject. Scientific publications on bee products were identified by a literature search on Pubmed, Scopus and Google Scholar. There is a lot of evidence regarding the use of honey for oral mucositis due to chemotherapy or radiotherapy or a combination of both. Unfortunately, the quality of several meta-analyses on the topic is very low. There is some evidence on propolis, a little on royal jelly and none whatsoever on pollen and other bee products like apilarnil or bee venom. Bee products such as honey, propolis and royal jelly may be well suited to be integrated into a general concept for the prevention and treatment of oral mucositis which should also include other established concepts like oral care, oral cryotherapy, topical vitamin E and low-level-laser therapy. Bee products could become an integral part in the treatment of chemotherapy, radiotherapy and radio chemotherapy. High-quality meta-analyses and further studies, especially on the combinations of various strategies, are needed.


Assuntos
Abelhas/química , Estomatite/economia , Estomatite/prevenção & controle , Administração Tópica , Animais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/uso terapêutico , Mel , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Própole/administração & dosagem , Própole/uso terapêutico , Vitamina E/administração & dosagem , Vitamina E/uso terapêutico
3.
BMC Complement Altern Med ; 19(1): 175, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299973

RESUMO

BACKGROUND: Skin injury is inevitable in daily life. In recent years, with the increasing morbidity of diseases such as diabetes and metabolic disorders, chronic wounds have become a considerable challenge in clinical practice. Royal jelly, reported to have multifarious biological and physiological properties, has been used as a remedy for a variety of wounds since ancient times. However, the active components and mechanisms underlying the wound-healing properties of royal jelly are still largely unknown. METHODS: Water-soluble proteins of royal jelly were fractionated and investigated for the proliferative and migratory effects on human epidermal keratinocytes (HaCaT) in an in vitro wound healing model. The proteins present in bioactive fractions were characterised and quantified using Label-free protein quantification method. The potential functions of these proteins in biological systems were further analysed using bioinformatic tools. RESULTS: A protein fraction, mainly containing major royal jelly proteins 2 (MRJP2), MRJP3 and MRJP7, stimulated proliferative and migratory activities in HaCaT cells without visible cytotoxicity. It exerted the greatest effects on the growth of HaCaT cells in the first 48 h. Furthermore, when treated with this protein fraction, the closure rates of the in vitro scratch wound were significantly increased. Functional analysis indicated that MRJP2, MRJP3 and MRJP7 were associated with carbohydrate transport and metabolism. CONCLUSIONS: We fractionated the water-soluble proteins of royal jelly and identified one fraction (Fraction 2) that induced both proliferative and migratory effects on a human epidermal keratinocyte cell line. Major royal jelly proteins (MRJP2, MRJP3 and/or MRJP7) were speculated to possess potential wound-healing bioactivity. This is the first report that royal jelly may improve wound closure via MRJP-induced cellular proliferation and migration. These proteins may be valuable lead compounds for the development of novel wound healing medications. Our findings would facilitate better understanding of the wound repair mechanisms of royal jelly.


Assuntos
Ácidos Graxos/química , Proteínas de Insetos/uso terapêutico , Queratinócitos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Abelhas , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/uso terapêutico , Humanos , Proteínas de Insetos/isolamento & purificação
4.
Methodist Debakey Cardiovasc J ; 15(1): 32-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049147

RESUMO

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins remain the first-line therapy for patients with elevated LDL-C and increased risk. However, many at-risk patients do not achieve adequate LDL-C lowering with statin monotherapy or do not tolerate statins because of side effects. Recent cardiovascular outcome trials involving ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated efficacy of nonstatin therapies in further reducing LDL-C levels and ASCVD risk. This review highlights the available nonstatin therapeutic options and explores important novel therapeutic approaches currently under development.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/genética , Ezetimiba/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
5.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083403

RESUMO

HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Graxos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactonas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/uso terapêutico , Everolimo/farmacologia , Everolimo/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Lactonas/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , Células PC-3 , Transdução de Sinais/efeitos dos fármacos , Streptomyces/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Am J Chin Med ; 47(4): 727-750, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31094213

RESUMO

Cancer management is a worldwide challenge. In addition to effective cancer therapies like chemotherapy, radiotherapy and surgery, treatment based on traditional Chinese medicine (TCM) and combined TCM with western medicine has gradually gained attention in Oriental countries. One potential TCM approach using extracted fatty oils, containing fatty acids which are important active ingredients with a variety of pharmacological activities, makes significant contributions to cancer treatment. The strategies of treating cancer with the fatty oils of TCM were classified into "Fuzheng", which usually associates with improving immunity, represented by coix seed oil. The other classification is "Quxie", which relates to inducing apoptosis of cancer cells, and is represented by Brucea javanica oil. Compared with other active substances, the literature about anticancer fatty oils is relatively limited, and most of them focus on the composition and other biological activities without a systematic review. Therefore, based on the theories of "Fuzheng" and "Quxie" in TCM, in this paper, the anticancer effects of fatty oils have been reviewed. The chemical composition, anticancer mechanism, listed drugs, studying dosage form and clinical application of fatty oils have also been discussed. In summary, since there are different types and abundance of fatty oils among botanicals, anticancer effects of fatty oils can be achieved through two TCM theory-based strategies. We hoped that this review paper can reveal the anticancer potential of fatty oils and provide a reference for future related studies.


Assuntos
Medicamentos de Ervas Chinesas/química , Ácidos Graxos/uso terapêutico , Glicerol/uso terapêutico , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológico , Óleos Vegetais/química , Óleos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/farmacologia , Glicerol/química , Glicerol/isolamento & purificação , Glicerol/farmacologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Fitoterapia , Óleos Vegetais/isolamento & purificação , Óleos Vegetais/farmacologia
7.
Top Companion Anim Med ; 35: 18-25, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31122683

RESUMO

The aim of this exploratory study was to evaluate the efficacy of a periophthalmic cream of a pool of fatty acids (FAG®) in association with 0.15% hyaluronate eye drops in alleviating the clinical symptoms of keratoconjunctivitis sicca (KCS) in a case series of dogs. The study was conducted on 10 dogs diagnosed with idiopathic KCS. All dogs had been previously treated with topical tobramycin alone, which had been ineffective in improving clinical signs. The affected eyes were treated with 2 applications daily of a periophthalmic cream of FAG® and 1 drop 3 times a day of 0.15% of hyaluronate eye drops for 8 weeks. Schirmer tear test I (STT I) values were recorded and ocular signs (conjunctival hyperemia, ocular discharge, corneal opacity, vascularization and pigmentation, and discomfort level) were collected, scored on a 3-point scale (grade 0, grade 1, and grade 2). Differences between scores and STT data recorded at baseline and at 8 weeks of therapy were statistically analysed. The effect of treatment was pronounced (increase in STT values by more than 4 mm/min, no signs of inflammation) in 8/18 eyes; moderate (increase in STT values of 3-4 mm/min or mild improvement in signs of corneal/conjunctival inflammation) in 3/18 eyes; and unsatisfactory in 7 of 18 eyes. Median of STT values significantly improved compared with baseline levels, while statistically significant decreases in clinical-sign scores of conjunctival hyperemia, ocular discharge, and discomfort were recorded. However, in moderate and advanced stages, reduction of neovascularization or corneal pigmentation was not observed throughout the treatment period. No noticeable adverse reactions were recorded. Preliminary results indicate that the application of periocular FAG and topical 0.15% hyaluronate eye drops may be a suitable treatment for KCS in dogs in selected cases. A larger comparative study is necessary to further confirm these findings.


Assuntos
Doenças do Cão/tratamento farmacológico , Ácidos Graxos/uso terapêutico , Ácido Hialurônico/uso terapêutico , Ceratoconjuntivite Seca/veterinária , Animais , Cães , Ácidos Graxos/administração & dosagem , Feminino , Ácido Hialurônico/administração & dosagem , Ceratoconjuntivite Seca/tratamento farmacológico , Masculino , Soluções Oftálmicas/uso terapêutico
8.
Am J Clin Nutr ; 109(Suppl_7): 852S-871S, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982869

RESUMO

BACKGROUND: Proper nutrition during early life is critical for growth and development. OBJECTIVES: The aim was to describe systematic reviews conducted by the Nutrition Evidence Systematic Review team for the USDA and the Department of Health and Human Services Pregnancy and Birth to 24 Months Project to answer the following: What is the relation between 1) timing of introduction of complementary foods and beverages (CFBs) or 2) types and/or amounts of CFBs consumed and micronutrient status (iron, zinc, vitamin D, vitamin B-12, folate, and fatty acid status)? METHODS: A literature search identified articles from developed countries published from January 1980 to July 2016 that met the inclusion criteria. Data were extracted and risk of bias assessed. Evidence was qualitatively synthesized to develop a conclusion statement, and the strength of the evidence was graded. RESULTS: Nine articles addressed the timing of CFB introduction and 31 addressed types or amounts or both of CFBs. Moderate evidence suggests that introducing CFBs at age 4 mo instead of 6 mo offers no advantages or disadvantages in iron status among healthy full-term infants. Evidence is insufficient on the timing of CFB introduction and other micronutrient status outcomes. Strong evidence suggests that CFBs containing iron (e.g., meat, fortified cereal) help maintain adequate iron status or prevent deficiency in the first year among infants at risk of insufficient iron stores or low intake. Benefits for infants with sufficient iron stores (e.g., infant formula consumers) are less clear. Moderate evidence suggests that CFBs containing zinc (e.g., meat, fortified cereal) support zinc status in the first year and CFB fatty acid composition influences fatty acid status. Evidence is insufficient with regard to types and amounts of CFBs and vitamin D, vitamin B-12, and folate status, or the relation between lower-iron-containing CFBs and micronutrient status. CONCLUSIONS: Several conclusions on CFBs and micronutrient status were drawn from these systematic reviews, but more research that addresses specific gaps and limitations is needed.


Assuntos
Deficiências Nutricionais/sangue , Dieta , Comportamento Alimentar , Alimentos Infantis , Fenômenos Fisiológicos da Nutrição do Lactente , Micronutrientes/sangue , Estado Nutricional , Bebidas , Aleitamento Materno , Deficiências Nutricionais/etiologia , Deficiências Nutricionais/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/sangue , Ácidos Graxos/uso terapêutico , Alimentos Fortificados , Humanos , Lactente , Fórmulas Infantis , Saúde do Lactente , Micronutrientes/administração & dosagem , Micronutrientes/uso terapêutico , Oligoelementos/administração & dosagem , Oligoelementos/sangue , Oligoelementos/uso terapêutico , Vitaminas/administração & dosagem , Vitaminas/sangue , Vitaminas/uso terapêutico
9.
Complement Ther Med ; 43: 20-27, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30935531

RESUMO

Diabetes mellitus is one of the most common endocrine disorders in the world. This systematic review was conducted with focus on the current knowledge on the effect of royal jelly on metabolic variables in diabetes mellitus. PubMed, Scopus, Embase, ProQuest and Google Scholar databases were searched from inception until June 2018. All clinical trials and animal studies that evaluated the effects of royal jelly on diabetes mellitus, and were published in English-language journals were eligible. Studies that provided insufficient outcomes were excluded. Out of 522 articles found in the search, only twelve articles were eligible for analysis. Seven studies showed a significant reduction in FBS, and one reported HbA1c decrease following royal jelly supplementation. Although royal jelly supplementation resulted in significant reductions in HOM A-I R in three studies, the findings on insulin levels were controversial. In addition, royal jelly substantially improved serum levels of triglycerides, cholesterol, HDL, LDL, VLDL and Apo-A1 in diabetes mellitus. In addition, royal jelly resulted in a decrease oxidative stress indicators and increase antioxidant enzymes levels. In conclusion, royal jelly could improve glycemic status, lipid profiles and oxidative stress in diabetes mellitus. However, exploring the underlying mechanisms warrants further studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos/uso terapêutico , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Colesterol/sangue , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/sangue , Humanos , Lipídeos/sangue , Triglicerídeos/sangue
10.
N Engl J Med ; 380(11): 1022-1032, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865796

RESUMO

BACKGROUND: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy. METHODS: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks. RESULTS: The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy. CONCLUSIONS: In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).


Assuntos
LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Idoso , Apolipoproteínas B/sangue , Proteína C-Reativa/análise , Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Resultado do Tratamento
11.
N Engl J Med ; 380(11): 1033-1042, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865797

RESUMO

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).


Assuntos
ATP Citrato (pro-S)-Liase/genética , Doenças Cardiovasculares/genética , LDL-Colesterol/sangue , Predisposição Genética para Doença , Hidroximetilglutaril-CoA Redutases/genética , Análise da Randomização Mendeliana , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Diabetes Mellitus/genética , Ácidos Dicarboxílicos/farmacologia , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/farmacologia , Ácidos Graxos/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Lipoproteínas/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Neoplasias/genética , Razão de Chances , Risco , Triglicerídeos/sangue
12.
Expert Opin Pharmacother ; 20(7): 791-803, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810432

RESUMO

INTRODUCTION: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/tratamento farmacológico , Proteína C-Reativa/metabolismo , Ensaios Clínicos como Assunto , Ácidos Dicarboxílicos/efeitos adversos , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Ácidos Graxos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fígado/metabolismo
13.
Kardiol Pol ; 77(2): 207-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740643

RESUMO

BACKGROUND: Due to the myopathic adverse events of statins, safer alternatives are being studied. Bempedoic acid (ETC-1002) is a novel low-density lipoprotein cholesterol (LDL-C)-lowering agent, currently under trial in hypercholesterolaemic patients. AIM: To investigate the tolerability and efficacy of ETC-1002 in hypercholesterolaemic patients through a systematic review of published randomised controlled trials (RCTs). METHODS: Five databases were searched for RCTs that investigated the safety and efficacy of ETC-1002 in hypercholesterol-aemic patients. The retrieved search results were screened, and then data were extracted and analysed (as mean difference [MD] or odds ratio [OR]) using the RevMan software. RESULTS: Five RCTs (625 hypercholesterolaemic patients) were identified. ETC-1002 was superior to placebo in terms of percent-age changes from baseline in serum levels of LDL-C (MD -26.58, 95% confidence interval [CI] -35.50 to -17.66, p < 0.0001), non-high-density lipoprotein cholesterol (MD -21.54, 95% CI -28.48 to -14.6, p < 0.00001), and apolipoprotein-B (MD -15.97, 95% CI -19.36 to -12.57, p < 0.0001). When compared to ezetimibe, ETC-1002 was superior in reducing LDL-C (-30.1 ± 1.3 vs. -21.1 ± 1.3). Regarding safety, ETC-1002 did not increase the risk of all adverse events (OR 0.58, 95% CI 0.37-0.91, p = 0.02) and arthralgia (OR 0.32, 95% CI 0.13-0.81, p = 0.02) compared to placebo. All other adverse events including myalgia, headache, and urinary tract infections were similar between ETC-1002 and placebo groups. The evidence certainty in the assessed outcomes was moderate to high except for lipoprotein(a), free fatty acids, and very low-density lipoprotein particle number (very low certainty). CONCLUSIONS: ETC-1002 is a safe and effective lipid-lowering agent and may be a suitable alternative in statin-intolerant pa-tients. Well-designed studies are needed to explore the long-term safety and efficacy of ETC-1002 in these patients.


Assuntos
Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Idoso , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Ezetimiba/efeitos adversos , Ezetimiba/uso terapêutico , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/sangue , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Circ Res ; 124(3): 386-404, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30702996

RESUMO

Several new or emerging drugs for dyslipidemia owe their existence, in part, to human genetic evidence, such as observations in families with rare genetic disorders or in Mendelian randomization studies. Much effort has been directed to agents that reduce LDL (low-density lipoprotein) cholesterol, triglyceride, and Lp[a] (lipoprotein[a]), with some sustained programs on agents to raise HDL (high-density lipoprotein) cholesterol. Lomitapide, mipomersen, AAV8.TBG.hLDLR, inclisiran, bempedoic acid, and gemcabene primarily target LDL cholesterol. Alipogene tiparvovec, pradigastat, and volanesorsen primarily target elevated triglycerides, whereas evinacumab and IONIS-ANGPTL3-LRx target both LDL cholesterol and triglyceride. IONIS-APO(a)-LRx targets Lp(a).


Assuntos
Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Benzimidazóis/uso terapêutico , Caproatos/uso terapêutico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Ácidos Dicarboxílicos/uso terapêutico , Dislipidemias/sangue , Ezetimiba/uso terapêutico , Ácidos Graxos/uso terapêutico , Terapia Genética , Humanos , Hipertrigliceridemia/tratamento farmacológico , Lipoproteína(a)/sangue , Oligonucleotídeos/uso terapêutico , RNA Interferente Pequeno/uso terapêutico
16.
Medicina (Kaunas) ; 55(2)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678228

RESUMO

Background and objectives: Oral mucositis is one of the main adverse events of cancer treatment with chemotherapy or radiation therapy. It presents as erythema, atrophy or/and ulceration of oral mucosa. It occurs in almost all patients, who receive radiation therapy of the head and neck area and from 20% to 80% of patients who receive chemotherapy. There are few clinical trials in the literature proving any kind of treatment or prevention methods to be effective. Therefore, the aim of this study is to perform systematic review of literature and examine the most effective treatment and prevention methods for chemotherapy or/and radiotherapy induced oral mucositis. Materials and methods: Clinical human trials, published from 1 January 2007 to 31 December 2017 in English, were included in this systematic review of literature. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol was followed while planning, providing objectives, selecting studies and analyzing data for this systematic review. "MEDLINE" and "PubMed Central" databases were used to search eligible clinical trials. Clinical trials researching medication, oral hygiene, cryotherapy or laser therapy efficiency in treatment or/and prevention of oral mucositis were included in this systematic review. Results: Results of the studies used in this systematic review of literature showed that laser therapy, cryotherapy, professional oral hygiene, antimicrobial agents, Royal jelly, L. brevis lozenges, Zync supplementation and Benzydamine are the best treatment or/and prevention methods for oral mucositis. Conclusions: Palifermin, Chlorhexidine, Smecta, Actovegin, Kangfuxin, L. brevis lozenges, Royal jelly, Zync supplement, Benzydamine, cryotherapy, laser therapy and professional oral hygiene may be used in oral mucositis treatment and prevention.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Radioterapia/efeitos adversos , Estomatite/etiologia , Estomatite/terapia , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Crioterapia , Ácidos Graxos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Terapia a Laser , Higiene Bucal , Estomatite/prevenção & controle
17.
Andrologia ; 51(3): e13213, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30548301

RESUMO

Royal jelly (RJ) as an antioxidant has been shown to have attenuated oxidative stress damages in reproductive organs. The objective was carried out the effects of RJ on sperm characteristics, sperm malondialdehyde (MDA) concentration and in vitro fertilisation (IVF) outcome in heat stress (HS) exposed male rats. Forty-eight male rats were randomly divided into eight groups; group 1 received normal saline, group 2 received RJ (100 mg kg-1  day-1 ; PO), groups 3, 4 and 5 were heat-stressed (43, 39 and 37°C for 20 min per day respectively) and groups 6, 7 and 8 were heat-stressed along with RJ (43, 39 and 37°C for 20 min per day, respectively, plus RJ at a dose of 100 mg kg-1  day-1 ; PO). The HS was induced through immersion of experimental rat scrotums in a water bath. After 48 days, the HS induced remarkable diminish in sperm motility, viability and fertilising potential along with reduced blastulation rate and enhanced sperm chromatin abnormality, MDA levels and DNA damage. Nevertheless, RJ co-administration improved sperm characteristics and early embryo development as well as sperm lipid peroxidation level. Our data suggest that RJ can effectively ameliorate the experimental HS-induced infertility in rats through MDA concentration restoration and sperm characteristics and pre-implantation embryo development improvement.


Assuntos
Ácidos Graxos/uso terapêutico , Transtornos de Estresse por Calor/complicações , Infertilidade Masculina/prevenção & controle , Substâncias Protetoras/uso terapêutico , Motilidade Espermática/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácidos Graxos/farmacologia , Transtornos de Estresse por Calor/metabolismo , Resposta ao Choque Térmico , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo
18.
Cardiol Rev ; 27(1): 49-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29939848

RESUMO

Bempedoic acid (BA; ETC-1002) is a new agent that reduces cholesterol synthesis through inhibition of adenosine triphosphate citrate lyase, an enzyme upstream from 3-hydroxy-3-methylglutaryl-coenzyme A. In animal models, BA also influences fatty acid synthesis, but in humans, its role is limited primarily to lowering low-density lipoprotein cholesterol (LDL-C). In early clinical trials, BA was well tolerated and without major side effects. Alone or in various combinations with atorvastatin and/or ezetimibe, LDL-C lowering ranged from 17% to 64%. In addition, BA lowers levels of non-high-density lipoprotein cholesterol, C-reactive protein, and apolipoprotein B. Statins are first-line agents for primary and secondary prevention of cardiovascular disease. However, muscle-related side effects and other problems such as elevated liver enzymes may limit their use. In addition, LDL-C lowering beyond that provided by statin therapy alone may be needed. BA may be useful in either of these scenarios, as it is relatively free of muscle-related side effects and appears to enhance LDL-C lowering beyond that achieved with statin monotherapy. Phase 3 trials and one outcomes study are currently under way to better define this agent's potential clinical role.


Assuntos
Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Humanos , Hipolipemiantes/farmacologia
19.
Int J Mol Sci ; 19(10)2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30347885

RESUMO

Royal jelly (RJ) is a glandular secretion produced by worker honeybees and is a special food for the queen honeybee. It results in a significant prolongation of the lifespan of the queen honeybee compared with the worker honeybees through anti-inflammatory, anti-oxidant and anti-microbial activities. Consequently, RJ is used as cosmetic and dietary supplement throughout the world. In addition, in vitro studies and animal experiments have demonstrated that RJ inhibits cell proliferation and stimulates apoptosis in various types of malignant cells and affects the production of various chemokines, anti-oxidants and growth factors and the expression of cancer-related molecules in patients with malignancies, especially in patients treated with anti-cancer agents. Therefore, RJ is thought to exert anti-cancer effects on tumor growth and exhibit protective functions against drug-induced toxicities. RJ has also been demonstrated to be useful for suppression of adverse events, the maintenance of the quality of life during treatment and the improvement of prognosis in animal models and patients with malignancies. To understand the mechanisms of the beneficial effects of RJ, knowledge of the changes induced at the molecular level by RJ with respect to cell survival, inflammation, oxidative stress and other cancer-related factors is essential. In addition, the effects of combination therapies of RJ and other anti-cancer agents or natural compounds are important to determine the future direction of RJ-based treatment strategies. Therefore, in this review, we have covered the following five issues: (1) the anti-cancer effects of RJ and its main component, 10-hydroxy-2-decenoic acid; (2) the protective effects of RJ against anti-cancer agent-induced toxicities; (3) the molecular mechanisms of such beneficial effects of RJ; (4) the safety and toxicity of RJ; and (5) the future directions of RJ-based treatment strategies, with a discussion on the limitations of the study of the biological activities of RJ.


Assuntos
Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Ácidos Graxos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Ácidos Graxos/efeitos adversos , Ácidos Graxos/química , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Monoinsaturados/farmacologia , Humanos
20.
Molecules ; 23(10)2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262731

RESUMO

Epigallocatechin-3-O-gallate (EGCG) is the major catechin component of green tea (Cameria sinensis), and is known to possess antiviral activities against a wide range of DNA viruses and RNA viruses. However, few studies have examined chemical modifications of EGCG in terms of enhanced antiviral efficacy. This paper discusses which steps of virus infection EGCG interferes with, citing previous reports. EGCG appears most likely to inhibits the early stage of infections, such as attachment, entry, and membrane fusion, by interfering with viral membrane proteins. According to the relationships between structure and antiviral activity of catechin derivatives, the 3-galloyl and 5'-OH group of catechin derivatives appear critical to antiviral activities. Enhancing the binding affinity of EGCG to virus particles would thus be important to increase virucidal activity. We propose a newly developed EGCG-fatty acid derivative in which the fatty acid on the phenolic hydroxyl group would be expected to increase viral and cellular membrane permeability. EGCG-fatty acid monoesters showed improved antiviral activities against different types of viruses, probably due to their increased affinity for virus and cellular membranes. Our study promotes the application of EGCG-fatty acid derivatives for the prevention and treatment of viral infections.


Assuntos
Antivirais/uso terapêutico , Catequina/análogos & derivados , Ácidos Graxos/uso terapêutico , Viroses/tratamento farmacológico , Fenômenos Fisiológicos Virais , Animais , Antivirais/química , Catequina/química , Catequina/uso terapêutico , Ácidos Graxos/química , Humanos , Viroses/metabolismo , Viroses/patologia
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