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1.
Clin Dermatol ; 38(4): 462-466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972604

RESUMO

The human genome project yielded a compendium of genetic material that has allowed rapid advancement both in the technique of whole exome sequencing and also in the ability to identify single gene defects. The next generation of genetics has investigated how these genes interact in the development of disease, identifying pathways of illness and end organ tissue abnormal development. From the knowledge of single genes and pathways of genodermatosis development arises the opportunity to produce genetic therapies. This contribution reviews some of the exciting, emerging genetic therapies in genodermatoses.


Assuntos
Dermatopatias Genéticas/terapia , Administração Tópica , Anticolesterolemiantes/administração & dosagem , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/terapia , Epidermólise Bolhosa/diagnóstico , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/terapia , Edição de Genes , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Transdução de Sinais/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Ustekinumab/uso terapêutico , Sequenciamento Completo do Exoma
2.
Lancet Gastroenterol Hepatol ; 5(7): 649-657, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389183

RESUMO

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ezetimiba/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Canadá/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Vírus de RNA/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Transplantes/virologia , Carga Viral/estatística & dados numéricos
3.
PLoS One ; 15(4): e0231582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302327

RESUMO

Atherosclerosis, the predominant cause of death in well-resourced countries, may develop in the presence of plasma lipid levels within the normal range. Inflammation may contribute to lesion development in these individuals, but the underlying mechanisms are not well understood. Transgenic mice expressing α-def-1 released from activated neutrophils develop larger lipid and macrophage-rich lesions in the proximal aortae notwithstanding hypocholesterolemia caused by accelerated clearance of α-def-1/low-density lipoprotein (LDL) complexes from the plasma. The phenotype does not develop when the release of α-def-1 is prevented with colchicine. However, ApoE-/- mice crossed with α-def-1 mice or given exogenous α-def-1 develop smaller aortic lesions associated with reduced plasma cholesterol, suggesting a protective effect of accelerated LDL clearance. Experiments were performed to address this seeming paradox and to determine if α-def-1 might provide a means to lower cholesterol and thereby attenuate atherogenesis. We confirmed that exposing ApoE-/- mice to α-def-1 lowers total plasma cholesterol and decreases lesion size. However, lesion size was larger than in mice with total plasma cholesterol lowered to the same extent by inhibiting its adsorption or by ingesting a low-fat diet. Furthermore, α-def-1 levels correlated independently with lesion size in ApoE-/- mice. These studies show that α-def-1 has competing effects on atherogenesis. Although α-def-1 accelerates LDL clearance from plasma, it also stimulates deposition and retention of LDL in the vasculature, which may contribute to development of atherosclerosis in individuals with normal or even low plasma levels of cholesterol. Inhibiting α-def-1 may attenuate the impact of chronic inflammation on atherosclerotic vascular disease.


Assuntos
Aorta/patologia , Aterosclerose/patologia , Colesterol/sangue , alfa-Defensinas/metabolismo , Animais , Anticolesterolemiantes/administração & dosagem , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/metabolismo , Colesterol/metabolismo , Resina de Colestiramina/administração & dosagem , Colchicina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Knockout para ApoE , Camundongos Transgênicos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , alfa-Defensinas/genética
4.
Rev Med Liege ; 75(4): 260-264, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32267116

RESUMO

LDL cholesterol targets are increasingly strict in recent international guidelines, especially in patients at very high or high cardiovascular risk. To reach these targets, it is recommended to use a potent statin, with a titration up to the maximal tolerated dose and, if not sufficient, to combine ezetimibe, a medication that blocks the intestinal absorption of cholesterol. This association allows reduce the dose of statin, while keeping an excellent cholesterol-lowering efficacy and favouring a good tolerance profile. This article describes the characteristics of a fixed-dose combination of rosuvastatin, the most potent statin, and ezetimibe, commercialized in Belgium under the trade name Myrosor®.


Assuntos
Anticolesterolemiantes , Ezetimiba , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Rosuvastatina Cálcica , Anticolesterolemiantes/administração & dosagem , Bélgica , LDL-Colesterol , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Humanos , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Resultado do Tratamento
5.
Int J Nanomedicine ; 15: 1335-1347, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184589

RESUMO

Background: Atorvastatin calcium (AT) is an ocular anti-inflammatory with limited bioavailability when taken orally due to its low solubility in low pH and extensive first-pass effect. To overcome these problems, AT was entrapped in polymeric nanoparticles (NPs) to improve surface properties and sustained release, in addition to achieving site-specific action. Methods: AT was entrapped in chitosan (CS)-coated polylactic-co-glycolic acid (PLGA) NPs to form AT-PLGA-CS-NPs (F1). F1 and free AT were embedded in thermosensitive Pluronic®127-hydroxypropyl methylcellulose (HPMC) to form thermosensitive gels (F2) and (F3) while F4 is AT suspension in water. F1 was assessed for size, surface charge, polydispersity index (PDI), and morphology. F2 and F3 were examined for gelation temperature, gel strength, pH, and viscosity. In vitro release of the four formulations was also investigated. The ocular irritancy and anti-inflammatory efficacy of formulations against prostaglandin E1-(PGE1) induced ocular inflammation in rabbits were investigated by counting the polymorphonuclear leukocytes (PMNs) and protein migrated in tears. Results: Oval F1 of 80.0-190.0±21.6 nm exhibited a PDI of 0.331 and zeta potential of 17.4±5.62 mV with a positive surface charge. F2 and F3 gelation temperatures were 35.17±0.22°C and 36.93±0.31°C, viscosity 12,243±0.64 and 9759±0.22 cP, gel strength 15.56±0.6 and 12.45±0.1 s, and pHs of 7.4±0.02 and 7.4±0.1, respectively. In vitro release of F1, F2, F3, and F4 were 48.21±0.31, 26.48±0.5, 84.76±0.11, and 100% after 24 hrs, respectively. All formulations were non-irritant. F2 significantly inhibited lid closure up to 3 h, PMN counts and proteins in tear fluids up to 5 h compared to other formulations. Conclusion: AT-PLGA-CS-NP thermosensitive gels proved to be successful ocular anti-inflammatory drug delivery systems.


Assuntos
Anti-Inflamatórios/farmacologia , Atorvastatina/farmacologia , Quitosana/química , Oftalmopatias/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacologia , Atorvastatina/administração & dosagem , Materiais Biocompatíveis/química , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Oftalmopatias/induzido quimicamente , Oftalmopatias/patologia , Géis/química , Inflamação/induzido quimicamente , Inflamação/patologia , Nanopartículas/química , Coelhos
6.
J Toxicol Environ Health A ; 83(3): 113-125, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116137

RESUMO

Simvastatin (SIM), a hypocholesterolaemic drug belonging to the statins group, is a widely prescribed pharmaceutical for prevention of cardiovascular diseases. Several studies showed that lipophilic statins, as SIM, cross the blood-brain barrier and interfere with the energy metabolism of the central nervous system in humans and mammalian models. In fish and other aquatic organisms, the effects of SIM on the brain energy metabolism are unknown, particularly following exposure to low environmentally relevant concentrations. Therefore, the present study aimed at investigating the influence of SIM on gene signaling pathways involved in brain energy metabolism of adult zebrafish (Danio rerio) following chronic exposure (90 days) to environmentally relevant SIM concentrations ranging from 8 ng/L to 1000 ng/L. Real-time PCR was used to determine the transcript levels of several genes involved in different pathways of the brain energy metabolism (glut1b, gapdh, acadm, accα, fasn, idh3a, cox4i1, and cox5aa). The findings here reported integrated well with ecological and biochemical responses obtained in a parallel study. Data demonstrated that SIM modulates transcription of key genes involved in the mitochondrial electron transport chain, in glucose transport and metabolism, in fatty acid synthesis and ß-oxidation. Further, SIM exposure led to a sex-dependent transcription profile for some of the studied genes. Overall, the present study demonstrated, for the first time, that SIM modulates gene regulation of key pathways involved in the energy metabolism in fish brain at environmentally relevant concentrations.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sinvastatina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/toxicidade , Bioensaio , Esquema de Medicação , Feminino , Humanos , Masculino , Sinvastatina/administração & dosagem , Poluentes Químicos da Água/administração & dosagem , Peixe-Zebra
7.
Am Heart J ; 222: 157-165, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32087417

RESUMO

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.


Assuntos
Adenilil Ciclases/genética , Aterosclerose/prevenção & controle , Estudo de Associação Genômica Ampla , Farmacogenética/métodos , Polimorfismo Genético , Medicina de Precisão/métodos , Compostos de Sulfidrila/administração & dosagem , Adenilil Ciclases/metabolismo , Anticolesterolemiantes/administração & dosagem , Aterosclerose/epidemiologia , Aterosclerose/genética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Testes Genéticos , Genótipo , Saúde Global , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
8.
J Am Coll Cardiol ; 75(6): 565-574, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32057369

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. OBJECTIVES: The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). METHODS: In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. RESULTS: In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. CONCLUSIONS: Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/sangue , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Stroke ; 51(4): 1231-1239, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078484

RESUMO

Background and Purpose- The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of <70 mg/dL to reduce the risk of cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature or aortic arch plaque >4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods- One thousand seventy-three French patients were assigned to <70 mg/dL (1.8 mmol/L) and 1075 to 100±10 mg/dL (90-110 mg/dL, 2.3-2.8 mmol/L). To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe on top if needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization and vascular death. Results- After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57-0.94]; P=0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% (P=0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% (P=0.023). The primary outcome or intracranial hemorrhage was reduced by 25% (P=0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53-2.62]; P=0.70). Conclusions- After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of <70 mg/dL during 5.3 years avoided 1 subsequent major vascular event in 4 (number needed to treat of 30) and no increase in intracranial hemorrhage. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , LDL-Colesterol/sangue , Sistemas de Liberação de Medicamentos/tendências , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Anticolesterolemiantes/administração & dosagem , Isquemia Encefálica/diagnóstico por imagem , LDL-Colesterol/antagonistas & inibidores , Ezetimiba/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Fatores de Tempo
10.
Curr Pharm Biotechnol ; 21(9): 852-861, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065098

RESUMO

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.


Assuntos
Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Plásticos Biodegradáveis/química , Portadores de Fármacos/química , Maleatos/química , Polietilenos/química , Administração Cutânea , Animais , Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Técnicas In Vitro , Agulhas , Pele/metabolismo , Absorção Cutânea
11.
Expert Opin Pharmacother ; 21(5): 531-539, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036729

RESUMO

Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.


Assuntos
Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Ezetimiba/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Colesterol/sangue , LDL-Colesterol/sangue , Sinergismo Farmacológico , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Resultado do Tratamento , Triglicerídeos/sangue
12.
J Med Chem ; 63(10): 5031-5073, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31930920

RESUMO

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome. Although diet and exercise can dramatically improve NASH outcomes, significant lifestyle changes can be challenging to sustain. Pharmaceutical therapies could be an important addition to care, but currently none are approved for NASH. Here, we review the most promising targets for NASH treatment, along with the most advanced therapeutics in development. These include targets involved in metabolism (e.g., sugar, lipid, and cholesterol metabolism), inflammation, and fibrosis. Ultimately, combination therapies addressing multiple aspects of NASH pathogenesis are expected to provide benefit for patients.


Assuntos
Sistemas de Liberação de Medicamentos/tendências , Desenvolvimento de Medicamentos/tendências , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/química , Anticolesterolemiantes/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Obesidade/metabolismo , PPAR gama/agonistas , PPAR gama/química , Estrutura Terciária de Proteína
13.
Am Heart J ; 220: 203-212, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31841795

RESUMO

BACKGROUND: People living with human immunodeficiency virus (PLHIV) are at higher risk of atherosclerotic cardiovascular disease (ASCVD) due to traditional and HIV- or antiretroviral treatment (ART)-related risk factors. The use of high-intensity statin therapy is often limited by comorbidities and drug-drug interactions with ART. Herein, we present the design and baseline characteristics of the BEIJERINCK study, which will assess the safety and efficacy of evolocumab in PLHIV and hypercholesterolemia/mixed dyslipidemia. METHODS: Randomized, double-blind, placebo-controlled, multinational trial that investigates monthly subcutaneous evolocumab 420 mg versus placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia who are treated with maximally-tolerated statin therapy. The primary outcome is the baseline to week 24 percent change in low density lipoprotein cholesterol (LDL-C). Secondary outcomes include achievement of LDL-C < 70 mg/dL and percent change in other plasma lipid and lipoprotein levels. Safety will also be examined. RESULTS: This study enrolled and dosed 464 patients who had a mean age of 56.4 years and were mostly male (82.5%). Mean duration with HIV was 17.4 years, and, by design, HIV viral load at screening was ≤50 copies/mL. ASCVD was documented in 35.6% of patients. Mean LDL-C of enrolled patients at baseline was 133.3 mg/dL. Statin use was prevalent (79.3% overall) with 74.6% receiving moderate or high-intensity statins. In total, 20.7% of patients did not receive statins due to intolerance/contraindications. CONCLUSIONS: The BEIJERINCK study is the first clinical trial to examine the lipid-lowering efficacy and safety of a fully human PCSK9 monoclonal antibody inhibitor in a moderate/high cardiovascular risk population of PLHIV.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Infecções por HIV/complicações , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Valores de Referência , Carga Viral
14.
J Sci Food Agric ; 100(2): 705-713, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31599967

RESUMO

BACKGROUND: Despite the growing importance of probiotics apparent health benefits, an impediment to the use of new probiotic cultures is their safety. Hence there is a need to strictly examine the biosafety as well as health benefits of probiotics in in vivo model systems. RESULTS: In this study, two lactic acid bacterial (LAB) cultures Lactobacillus fermentum NCMR 2826 and FIX proven for their in vitro probiotic properties were investigated for their in vivo safety in Wistar rats. An acute toxicity study (14 days) with a high dose of biomass (1016 colony-forming units (CFU) mL-1 ) followed by a subchronic test for 13 weeks with oral feeding of the probiotic cultures in three different doses (107 , 108 and 1010 CFU mL-1 ) on a daily basis revealed the safety of the L. fermentum cultures. The probiotic feeding had no toxic effects on survival, body weight and food consumption with any of the dosages used throughout the treatment period. No statistically significant changes in relative organ weights and serum biochemical and hematological indices were found between the control and the probiotic fed animals. In addition to the safety attributes, the L. fermentum culture fed rats showed reduced serum cholesterol levels, macrovesicular steatosis and hepatocyte ballooning compared with control animals. Further, quantification of intestinal microbiota using real-time polymerase chain reaction (PCR) analysis from animal feces indicated a significant increase and stability of Lactobacillus and Bifidobacterium counts but a decrease of Escherichia coli numbers. CONCLUSION: This study of safety and beneficial features highlights the use of the two native L. fermentum isolates as potential probiotic food supplements. © 2019 Society of Chemical Industry.


Assuntos
Anticolesterolemiantes/administração & dosagem , Colesterol/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus fermentum/metabolismo , Probióticos/administração & dosagem , Animais , Anticolesterolemiantes/metabolismo , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Colesterol/sangue , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Lactobacillus fermentum/crescimento & desenvolvimento , Masculino , Probióticos/metabolismo , Ratos , Ratos Wistar
15.
J Am Acad Dermatol ; 82(1): 123-131, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31449901

RESUMO

BACKGROUND: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis. OBJECTIVE: To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis. METHODS: We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3 months. The response was evaluated and patients photographed at every visit. RESULTS: Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events. LIMITATIONS: Case series design with a small number of patients. CONCLUSION: Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors.


Assuntos
Anticolesterolemiantes/administração & dosagem , Carboxiliases/genética , Colesterol/administração & dosagem , Lovastatina/administração & dosagem , Poroceratose/tratamento farmacológico , Poroceratose/genética , Administração Cutânea , Adulto , Pré-Escolar , Combinação de Medicamentos , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Pomadas , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Adulto Jovem
16.
J Pharmacol Exp Ther ; 372(1): 54-62, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31649050

RESUMO

Obesity is a pathologic condition generated by an energy imbalance, that is, excess caloric consumption, leading to weight gain and metabolic disturbances characterized by adipose tissue inflammation and hyperglycemic conditions. In line with these observations, increasing evidence causally links inflammation, or the molecules and networks integral to inflammatory response, to the development of obesity and the complications that emerge from this pathology, such as cardiovascular, neurologic, respiratory, and metabolic illnesses, as well as sepsis and cancer. Not surprisingly, this chronic and abnormal metabolic background leads to constant derangements in innate and adaptive immunity. It is well known that high-density lipoprotein (HDL) possesses anti-inflammatory and antioxidant properties, and various studies have highlighted an emerging role of HDL in modulating immune function. The efficacy of synthetic HDL (sHDL) containing the recombinant form of apoA-IMilano (sHDL-apoA-IM), originating from the observation that carriers of this mutation have low levels of HDL cholesterol without increased atherosclerosis, has been largely proved in diverse animal models of atherosclerosis; however, the therapeutic use of sHDL-apoA-IM still needs clinical validation. One of the main limitations to the use of recombinant proteins in clinical studies lies in the unsustainable purification costs. Unpurified rice-milk-apoA-IM demonstrated anti-inflammatory and antiatherogenic properties in a mouse model, even though administrated by an unconventional way: by oral gavage. Additionally, recent data have uncovered new therapeutic applications for this sHDL-apoA-IM This review provides an overview of all potential application of sHDL-apoA-IM in some inflammatory-based diseases. SIGNIFICANCE STATEMENT: A recent study demonstrated that oral administration of rice-seed protein extracts containing the apoA-IM (i.e., the milk-apoA-IM) reduced atherosclerosis development in a mouse model. Moreover, the rice-milk-apoA-IM preserved both in vitro and in vivo anti-inflammatory properties, as observed when sHDL-apoA-IM was given by intravascular infusion. Besides, various studies suggested that sHDL-apoA-IM could positively affect other inflammatory-based diseases. Together, these data might represent a new starting point for "sHDL-apoA-IM-based therapies" in chronic degenerative disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/uso terapêutico , Aterosclerose/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Apolipoproteína A-I/administração & dosagem , Aterosclerose/prevenção & controle , Humanos
17.
Clín. investig. arterioscler. (Ed. impr.) ; 31(6): 271-277, nov.-dic. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-185153

RESUMO

Se presenta la cuarta actualización de las tablas de planificación terapéutica. Esta tabla es una sencilla herramienta de sobremesa que permite determinar la terapia hipocolesterolemiante oral más apropiada para su paciente, bien con monoterapia, bien con terapia combinada (estatinas más ezetimiba), teniendo en cuenta su colesterol ligado a lipoproteínas de baja densidad (c-LDL) de partida y el objetivo terapéutico a alcanzar. Estas indicaciones terapéuticas se basan en 2 principios fundamentales: la causalidad del c-LDL y que el efecto de protección cardiovascular depende del descenso del c-LDL. Se han diseñado como un código de colores que señala los fármacos que tienen la potencia necesaria para llevar a su paciente a objetivos terapéuticos. Se establecen unas recomendaciones sobre la estrategia a seguir para implementar el tratamiento más eficaz. También se muestra hasta qué niveles podemos esperar un descenso de c-LDL al añadir un inhibidor de PCSK9


This is the fourth update of the therapeutic planning tables. These tables are a simple desktop tool, to help in determining the most appropriate oral cholesterol-lowering therapy for patient. This can either be with monotherapy or combination therapy (statins plus ezetimibe), taking into account the patient LDL cholesterol (LDL-C) and the therapeutic objective to be achieved. These therapeutic indications are based on 2 fundamental principles: the causality of LDL-C, and that the effect of cardiovascular protection depends on the decrease in LDL-C. It is based on a colour code that indicates the drugs that have the necessary power to meet the therapeutic objectives of the patient. We provide some recommendations on the strategy to follow to implement the most effective treatment. It is assessed up to what levels a decrease in LDL-C can be expected by adding a PCSK9 inhibitor


Assuntos
Humanos , Anticolesterolemiantes/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Equivalência Terapêutica , Padrões de Referência , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/farmacologia , Valores de Referência
18.
Medicine (Baltimore) ; 98(48): e18147, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770254

RESUMO

INTRODUCTION: Neurosyphilis is a chronic infection of the central nervous system that is commonly found in adult with long latency periods. Neurosyphilis-attributed deaths in young patients have grown exponentially in the past decade, yet there have been few studies on the early stages of neurosyphilis. PATIENT CONCERNS: A young male patient with syphilitic cerebral arteritis was evaluated in our clinic for the clinical signs of progressive ischemic stroke. DIAGNOSIS: The progression of syphilitic cerebral arteritis was observed through computed tomography imaging, magnetic resonance imaging, magnetic resonance angiogram, and transcranial color Doppler. The pathological changes and clinical outcomes were reviewed. In this specific case, the development of syphilitic cerebral arteritis was dynamic, continuous, and rapid. The pathogenesis was related to Heubner arteritis, in which the formation of a mural thrombus (MT) causes the severe obstruction of blood flow without complete occlusion, leading to an increased risk of infarction. In this patient, formation of the MT resulted in the infarction of the smaller vessels and narrowing of the larger vessels. The partial dislodgment of the MT from the arterial wall of the larger vessels occluded the smaller vessels, leading to infarction. INTERVENTIONS: Standard pharmacotherapy for the treatment of the cerebral infarction and a single course of penicillin were applied. OUTCOMES: Muscle strength was recovered. The Glasgow Coma Scale score was 15, whereas the NIH Stroke Scale score was 0. The increase in blood flow of the right MCA was accompanied by severe stenosis with compensation of the anterior communicating artery. In addition, moderate to severe stenosis of the right vertebral artery and the basilar artery was suspected. There was a possibility that the right posterior communicating artery was recruited for compensation. CONCLUSION: Progressive stroke was the initial symptom of the neurosyphilis. Disease progression is rapid and difficult to control with a single course of penicillin.


Assuntos
Atorvastatina/administração & dosagem , Infarto Encefálico , Clopidogrel/administração & dosagem , Edaravone/administração & dosagem , Neurossífilis , Vasculite do Sistema Nervoso Central , Adulto , Anticolesterolemiantes/administração & dosagem , Infarto Encefálico/diagnóstico , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/etiologia , Infarto Encefálico/fisiopatologia , Humanos , Angiografia por Ressonância Magnética/métodos , Masculino , Força Muscular , Exame Neurológico/métodos , Fármacos Neuroprotetores/administração & dosagem , Neurossífilis/complicações , Neurossífilis/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana/métodos , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/etiologia
19.
Expert Opin Drug Saf ; 18(12): 1191-1201, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31623472

RESUMO

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have been developed since the discovery of the PCSK9 protein in 2003. In addition to background statin treatment, they reduce low-density lipoprotein cholesterol (LDL-C) to unprecedented levels and have shown encouraging results in improving cardiovascular events. Concerns regarding the safety of PCSK9 inhibitors and very low LDL-C have somewhat been allayed after several longer-term prospective studies.Areas covered: A comprehensive literature search was carried out including article searches in electronic databases (EMBASE, PUBMED, OVID) and reference lists of relevant articles. This review examines novel research concerning PCSK9 monoclonal antibodies and cardiovascular outcomes with a special focus on their safety and tolerability. The safety of very low LDL-C concentrations and the link between LDL-C lowering and diabetes is also discussed.Expert opinion: PCSK9 monoclonal antibodies when added to background statin therapy, lowers LDL-C to previously unattainable levels. This is safe with little undesirable effects and impacts positively on cardiovascular disease. Current guidance limits their use to primary prevention. Cost effectiveness should be taken into consideration before allowing a wider use of this new class of cholesterol lowering therapy and more data on their long-term safety is welcome.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Prevenção Primária , Pró-Proteína Convertase 9/imunologia
20.
Expert Opin Drug Metab Toxicol ; 15(11): 897-911, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31648563

RESUMO

Introduction: Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities.Area covered: Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins.Expert opinion: Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/epidemiologia
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