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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.
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
3.
J Coll Physicians Surg Pak ; 29(6): 502-504, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133144

RESUMO

OBJECTIVE: To compare the effect of combination therapies of topical 3% tranexamic acid versus topical 20% azelaic acid each combined with oral tranexamic acid in the treatment of melasma. STUDY DESIGN: Interventional comparative study. PLACE AND DURATION OF STUDY: Department of Dermatology, Sheikh Zayed Hospital, Rahim Yar Khan, from July 2017 to June 2018. METHODOLOGY: Cases of melasma diagnosed clinically (based upon history and the clinical findings of symmetrically distributed hyperpigmented macules and patches on the face), aged 12 to 50 years, were selected. The cases were divided into two groups by simple random sampling method. The cases in group A were treated by oral tranexamic acid (250 mg twice daily) with topical 3% tranexamic acid (twice daily). In group B, cases had oral tranexamic acid (250 mg twice daily) with topical 20% azelaic acid (daily) for six months. They were followed every second month upto 6 months and the efficacy was assessed on the basis of scores on MASI scale. RESULTS: In 100 patient, there was no significant difference in terms of mean MASI score at 2 and 4 months with p-value of 0.20 and 0.89, respectively. However, mean MASI score was significantly less in group A (6.06 ±5.06 vs. 10.62 ±7.43) in group B (p=0.001). In group A, 14 (28%) had excellent response, whereas in group B, 11 (22%) had excellent results. CONCLUSION: Combination of oral and topical 3% tranexamic acid is significantly better than oral tranexamic acid with 20% azelaic acid for treatment of melasma.


Assuntos
Antifibrinolíticos/administração & dosagem , Ácidos Dicarboxílicos/administração & dosagem , Melanose/tratamento farmacológico , Ácido Tranexâmico/administração & dosagem , Administração Cutânea , Administração Oral , Adulto , Antifibrinolíticos/uso terapêutico , Terapia Combinada , Fármacos Dermatológicos , Ácidos Dicarboxílicos/uso terapêutico , Feminino , Humanos , Síndromes Neurocutâneas/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento
4.
Dermatol Clin ; 37(2): 183-193, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850041

RESUMO

Therapeutic actives for acne have changed little in the last decade. Recognition that acne is an inflammatory condition, not an infectious one, has led to a call for reduction in antibiotic use. This has culminated in a re-evaluation of highly efficacious combination topical therapy and improved vehicle technology. Laser and light modalities, although not sufficiently studied for first-line use, show promise for the future. The role that diet plays in the initiation and continuation of acne is unclear but remains one of our patients' most frequently asked questions.


Assuntos
Acne Vulgar/terapia , Antibacterianos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Dietoterapia , Terapia com Luz de Baixa Intensidade , Fototerapia , Acne Vulgar/imunologia , Administração Cutânea , Administração Oral , Terapia Combinada , Dapsona/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Quimioterapia Combinada , Humanos , Inflamação , Retinoides/uso terapêutico
5.
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
6.
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
7.
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
8.
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
9.
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
10.
Drug Dev Ind Pharm ; 45(4): 642-650, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30642209

RESUMO

OBJECTIVE: To develop an azelaic acid (AzA)-loaded nanoemulsion with hyaluronic acid (HA) as a double targeting strategy to increase drug retention and tyrosinase inhibition activity. SIGNIFICANCE: Dermic melasma is a recalcitrant disease. Therefore, the development of new technologies that allow a deeper penetration in the skin while enhancing the efficacy of a safe and well-known dermatological active, like AzA, is a very promising alternative to improve the treatment of this disease. METHODS: An oil-in-water nanoemulsion was developed and characterized according to its droplet size distribution, zeta potential, pH value, drug content, encapsulation efficiency, spectroscopic characteristics, morphology, and stability. In vitro mushroom tyrosinase inhibition assay, cytotoxicity, and permeation studies were performed. A descriptive sensory evaluation was also carried out. RESULTS: Drug content was 10 mg/ml, particle size 419 ± 23 nm with monomodal distribution, encapsulation efficiency was 84.65%, zeta potential -10.9 ± 0.44 mV and pH 5.01 ± 0.01. The nanoemulsion was stable for 30 days (30 °C/65% RH). The nanoemulsion decreased tyrosinase activity and permeated through the skin, reaching viable epidermis and dermis and did not show signs of cytotoxicity. Sensory evaluation profile showed a higher spreadability with lesser whitening residue. CONCLUSION: The nanoemulsion presented characteristics within the nanoscale and reached the deeper layers of the skin while improving in vitro tyrosinase inhibition; hence, it could be a promising treatment to dermic melasma.


Assuntos
Fármacos Dermatológicos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/farmacologia , Preparações Clareadoras de Pele/farmacologia , Administração Cutânea , Animais , Sobrevivência Celular/efeitos dos fármacos , Fármacos Dermatológicos/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Emulsões , Voluntários Saudáveis , Humanos , Melanose/tratamento farmacológico , Monofenol Mono-Oxigenase/antagonistas & inibidores , Nanopartículas/química , Tamanho da Partícula , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Preparações Clareadoras de Pele/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Suínos
11.
PLoS One ; 14(1): e0208730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653511

RESUMO

The disruption of coordinated control between the brain, spinal cord and peripheral nervous system caused by spinal cord injury (SCI) leads to several secondary pathological conditions, including lower urinary tract dysfunction. In fact, urinary tract dysfunction associated with SCI is urinary dysfunction could be a consequence of a lack of neuroregeneration of supraspinal pathways that control bladder function. The object of the current research was to explore the effects of adelmidrol + sodium hyaluronate, on bladder damage generated after SCI in mice. Spinal cord was exposed via laminectomy, and SCI was induced by extradural compression at T6 to T7 level, by an aneurysm clip with a closing force of 24 g. Mice were treated intravesically with adelmidrol + sodium hyaluronate daily for 48 h and 7 days after SCI. Adelmidrol + sodium hyaluronate reduced significantly mast cell degranulation and down-regulated the nuclear factor-κB pathway in the bladder after SCI both at 48 h and 7days. Moreover, adelmidrol + sodium hyaluronate reduced nerve growth factor expression, suggesting an association between neurotrophins and bladder pressure. At 7 days after SCI, the bladder was characterized by a marked bacterial infection and proteinuria; surprisingly, adelmidrol + sodium hyaluronate reduced significantly both parameters. These data show the protective roles of adelmidrol + sodium hyaluronate on bladder following SCI, highlighting a potential therapeutic target for the reduction of bladder changes.


Assuntos
Ácidos Dicarboxílicos/uso terapêutico , Ácido Hialurônico/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Animais , Western Blotting , Imunofluorescência , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Traumatismos da Medula Espinal/metabolismo , Bexiga Urinária/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
12.
J Dermatolog Treat ; 30(6): 572-577, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29862871

RESUMO

Background: Combined azelaic acid (AA) and salicylic acid (SA) have not been previously used for acne. Objective: To compare the efficacy of this combination versus trichloroacetic acid (TCA) 25% peel in acne. Methods: Thirty-four patients were included in this trial. Patients received four sessions 2 weeks apart. The combined solution was applied to one side of the face, while TCA was applied to the other. Our outcomes were physician-reported clinical improvement, dermoscopic assessment of the erythema and patient's satisfaction. Results: After two sessions, a significant clinical improvement was observed in non-inflammatory lesions in the TCA-treated side-treated TCA and in inflammatory lesions in the SA/AA-treated side. At the end, both modalities led to significant improvement, with no significant difference in between. Patients reported more discomfort with the TCA-treated side. There was no significant different clinical improvement in both treated sides as regards SPT. Erythema improved in both sides. Patients were more satisfied by the SA/AA-treated side. Conclusion: Chemical peeling is effective in controlling mild-moderate acne in SPT III-IV. Combined SA 20% and AA 20% are recommended at early stage of treatment if patients have more inflammatory lesions, while TCA is recommended if patients have more non-inflammatory lesions.


Assuntos
Acne Vulgar/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácido Salicílico/uso terapêutico , Ácido Tricloroacético/uso terapêutico , Acne Vulgar/patologia , Adolescente , Adulto , Abrasão Química , Dermoscopia , Ácidos Dicarboxílicos/efeitos adversos , Eritema/tratamento farmacológico , Feminino , Humanos , Masculino , Satisfação do Paciente , Ácido Salicílico/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento , Ácido Tricloroacético/efeitos adversos , Adulto Jovem
14.
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
17.
Atherosclerosis ; 277: 195-203, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29910030

RESUMO

BACKGROUND AND AIMS: Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering. METHODS: This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C. RESULTS: The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups. CONCLUSIONS: Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.


Assuntos
LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ezetimiba/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Idoso , Biomarcadores/sangue , Canadá , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Regulação para Baixo , Quimioterapia Combinada , Europa (Continente) , Ezetimiba/efeitos adversos , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
18.
Dermatol Clin ; 36(2): 135-150, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29499797

RESUMO

Papulopustular rosacea is characterized by papules and pustules in the central facial region. We review the literature surrounding the treatment of papulopustular rosacea. PubMed, EMBASE, and Cochrane (Central) databases searches of articles published from 1980 to 2015 were performed using the MeSH terms or keywords "rosacea" and "clinical trial." Additional searches were performed to include rosacea and each treatment modality used. Topical metronidazole, azelaic acid, ivermectin, and oral doxycycline have the most robust data to support their use. Variation in assessment tools and a lack of clinical trial standardization makes comparison of therapeutic options difficult.


Assuntos
Anti-Infecciosos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Doxiciclina/uso terapêutico , Ivermectina/uso terapêutico , Metronidazol/uso terapêutico , Rosácea/tratamento farmacológico , Administração Cutânea , Ácidos Dicarboxílicos/administração & dosagem , Humanos , Ivermectina/administração & dosagem , Metronidazol/administração & dosagem
19.
Int J Mol Sci ; 19(3)2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29510576

RESUMO

Lung metastasis constitutes the leading cause of the death in patients with osteosarcoma. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) regulates the invasion and lung metastasis of osteosarcoma cells in a mouse model and as well as in clinical samples. In the present study, we examined the anti-metastatic effect of SK-216, a small compound PAI-1 inhibitor, in human 143B osteosarcoma cells. An in vitro study showed that SK-216 treatment suppressed invasion activity by inhibiting PAI-1 expression in 143B cells, but had no influence on their proliferation or migration. 143B cells treated with SK-216 exhibited reduced matrix metalloproteinase-13 (MMP-13) secretion in a dose-dependent manner. Moreover, intraperitoneal injection of SK-216 into mouse models resulted in downregulation of PAI-1 expression levels in the primary tumors and showed suppression of lung metastases without influencing the proliferative activity of the tumor cells in the primary lesions. These results indicate that SK-216, a PAI-1 inhibitor, may serve as a novel drug to prevent lung metastasis in human osteosarcoma.


Assuntos
Antineoplásicos/uso terapêutico , Benzoxazóis/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzoxazóis/administração & dosagem , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Ácidos Dicarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/farmacologia , Neoplasias Pulmonares/secundário , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo
20.
Annu Rev Med ; 69: 113-131, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29414257

RESUMO

Familial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hiperlipoproteinemia Tipo II/terapia , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Benzimidazóis/uso terapêutico , Caproatos/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Terapia Genética , Humanos , Oligonucleotídeos/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Resultado do Tratamento
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