Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
Mais filtros










Filtros aplicados
Base de dados
Intervalo de ano de publicação
1.
J Dairy Sci ; 103(2): 1559-1565, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785870

RESUMO

Aflatoxin is a potent carcinogen commonly found in animal feeds that can impair rumen fermentation at high concentrations; however, its effects at physiologically relevant concentrations are unknown. This study examined the effects of aflatoxin B1 (AFB1), with or without bentonite clay (CL) and Saccharomyces cerevisiae fermentation product (SCFP)-based sequestering agents on in vitro rumen fermentation and digestibility of a dairy cow TMR. Corn silage-based TMR (0.5 g, 17.3% crude protein and 1.67 Mcal/kg of net energy for lactation) was incubated in a rumen fluid-buffer inoculum (1:2 ratio; 50 mL) with the following treatments: (1) no additives (control); (2) control + 0.75 µg/L AFB1 (T); (3) T + 80 mg/L sodium bentonite clay (CL; Astra-Ben-20, Prince Agri Products Inc., Quincy, IL); or (4) CL + 14 mg/L SCFP (CL+SCFP; Diamond V, Cedar Rapids, IA). Ruminal fluid was collected 3 h after the morning feeding from 3 cannulated cows fed the same TMR, and rumen fluid from individual cows was used to prepare separate inocula. Each treatment was incubated in duplicate at 39°C for 0, 4, 8, 16, and 24 h in each of 3 runs. Adding T reduced total volatile fatty acid (VFA) concentration after 4 and 8 h and molar proportion of propionate after 4 and 24 h of incubation relative to control. Adding sequestering agents (CL and CL+SCFP) with T did not affect total VFA concentration after 4 or 8 h, but increased total VFA after 16 h and tended to increase molar proportion of propionate after 24 h compared with T. At 24 h, T had lower DM digestibility and higher NH3-N concentration compared with the control. Thus, AFB1, even at very low concentration (0.75 µg/L), had detrimental effects on rumen fermentation and subsequently DM digestibility of the TMR. Adding sequestering agents did not prevent negative effects of T on rumen fermentation within 8 h of incubation; however, sequestering agents were effective after 16 h of incubation.


Assuntos
Aflatoxina B1/toxicidade , Ração Animal , Bovinos , Venenos/toxicidade , Rúmen/efeitos dos fármacos , Aflatoxina B1/metabolismo , Ração Animal/análise , Animais , Bentonita/farmacologia , Dieta/veterinária , Feminino , Fermentação/efeitos dos fármacos , Lactação/fisiologia , Rúmen/metabolismo , Saccharomyces cerevisiae/metabolismo , Sequestrantes/farmacologia , Silagem/análise , Zea mays
2.
J Dairy Sci ; 103(2): 1431-1447, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785878

RESUMO

This study was conducted to examine the effects of clay (CL) and Saccharomyces cerevisiae fermentation product (SCFP) on the ruminal bacterial community of Holstein dairy cows challenged with aflatoxin B1 (AFB1). A second objective was to examine correlations between bacterial abundance and performance measures. Eight lactating dairy cows stratified by milk yield and parity were randomly assigned to 4 treatments in a 4 × 4 Latin square design with 2 replicate squares, four 33-d periods, and a 5-d washout between periods. The treatments included (1) control (basal diet, no additive); (2) T (control + 63.4 µg/kg AFB1, oral dose); (3) CL (T + 200 g/head per day of sodium bentonite clay, top-dress); and (4) CL+SCFP [CL + 19 g/head per day Diamond V NutriTek (Diamond V Inc., Cedar Rapids, IA) + 16 g/head per day MetaShield (Diamond V Inc.), top-dress]. Cows were adapted to diets containing no AFB1 from d 1 to 25 (predosing period). From d 26 to 30 (dosing period), AFB1 was orally dosed and then withdrawn for d 31 to 33 (withdrawal period). During the predosing period, compared with the control, feeding CL and CL+SCFP increased the relative abundance of the most dominant phylum, Bacteroidetes (55.1 and 55.8 vs. 50.6%, respectively), and feeding CL+SCFP increased Prevotella abundance (43.3 and 43.6 vs. 40.0%, respectively). During the dosing period, feeding AFB1 did not affect the ruminal bacterial community, but the relative abundance of Fibrobacteraceae increased with CL+SCFP compared with T (1.45 vs. 0.97%); Fibrobacter abundance also tended to increase with CL+SCFP compared with T and control, respectively (1.45 vs. 0.97 and 1.05%, respectively). Feeding AFB1 with or without CL or CL+SCFP did not affect ruminal pH or concentrations of NH3-N, total volatile fatty acids, or individual volatile fatty acids. Milk yield and milk component yields were positively correlated with the relative abundance of unclassified Succinivibrionaceae, unclassified YS2, or Coprococcus. Feed efficiency was positively correlated (r ≥ 0.30) with the relative abundance of unclassified YS2, Coprococcus, or Treponema. Feeding aflatoxin at 63 µg/kg, a common contamination level on farms, did not affect the abundance of dominant bacteria or rumen fermentation. When aflatoxin was fed, CL+SCFP increased the abundance of Fibrobacter, a major fibrolytic bacteria genus. Milk yield and DMI were positively correlated with abundance of Succinivibrionaceae and Coprococcus. Feed efficiency was positively correlated with abundance of Coprococcus, Treponema, and YS2. Future studies should speciate culture and determine the functions of the bacteria to elucidate their roles in the rumen and potential contribution to increasing the performance of dairy cows.


Assuntos
Aflatoxina B1/efeitos adversos , Bentonita/farmacologia , Bovinos/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Leite/metabolismo , Saccharomyces cerevisiae/química , Sequestrantes/farmacologia , Animais , Argila , Dieta/veterinária , Ácidos Graxos Voláteis/metabolismo , Feminino , Fermentação , Lactação , Paridade , Gravidez , Prevotella/efeitos dos fármacos , Prevotella/crescimento & desenvolvimento , Distribuição Aleatória
3.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554226

RESUMO

Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the treatment efficacy of drugs. In the present investigation, we hypothesized that extracellular albumin might orchestrate SeCs efficacy. Four SeCs representing distinct categories were selected to investigate their cytotoxicity, cellular uptake, and species transformation. Concomitant treatment of albumin greatly decreased cytotoxicity and cellular uptake of SeCs. Using both X-ray absorption spectroscopy and hyphenated mass spectrometry, we confirmed the formation of macromolecular conjugates between SeCs and albumin. Although the conjugate was still internalized, possibly via albumin scavenger receptors expressed on the cell surface, the uptake was strongly inhibited by excess albumin. In summary, the present investigation established the importance of extracellular albumin binding in determining SeCs cytotoxicity. Due to the fact that albumin content is higher in humans and animals than in cell cultures, and varies among many patient categories, our results are believed to have high translational impact and clinical implications.


Assuntos
Albuminas/química , Sequestrantes/química , Sequestrantes/farmacologia , Albuminas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Análise Espectral
4.
Drug Dev Ind Pharm ; 45(9): 1437-1443, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31107115

RESUMO

The purpose of the study was to develop and validate a high-performance liquid chromatography (HPLC) method which can be further applied to understand the mechanism, kinetics, isotherm, and thermodynamics of bile acid adsorption onto bile acid sequestrants. To investigate these properties a HPLC method was developed using peerless C-8 (150 x 4.6 mm, 5 µm) column with a detection wavelength of 200 nm and run time of about 12.5 min. Bile salts glycocholic (GC), glycochenodeoxycholic (GCDC), and taurodeoxycholic acid (TDC), were used and colesevelam hydrochloride was employed as the bile acid sequestrant. The calibration range was found linear from 10 to 6500 mgL-1 for GC and GCDC and 4to 2400 mg L-1 for TDC. The precision was less than 8.8% and accuracy was found well within the range of 85 to 115%. On treating the data with various established models, it was known that, the adsorption kinetics followed the pseudo second order equation indicating chemisorption mechanism. Equilibrium isotherms revealed that the linear form of Langmuir model was the best fit. The separation factor (RL) calculated revealed that the reaction is favorable and reversible. The positive value of heat of sorption (B) calculated from Temkin model indicated towards the exothermic nature of adsorption. The adsorption energy (E) calculated from Dubinin-Kaganer-Radushkevich model was found to be greater than 8 KJmol-1 conforming chemisorption mechanism. The Gibbs free energy calculated established the affinity of bile salts as TDC > GCDC > GC.


Assuntos
Ácidos e Sais Biliares/química , Sequestrantes/química , Adsorção , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , Termodinâmica
5.
Biotechnol Adv ; 37(3): 357-381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30768953

RESUMO

Numerous enzymes of biotechnological importance have been immobilized on magnetic nanoparticles (MNP) via random multipoint attachment, resulting in a heterogeneous protein population with potential reduction in activity due to restriction of substrate access to the active site. Several chemistries are now available, where the modifier can be linked to a single specific amino acid in a protein molecule away from the active-site, thus enabling free access of the substrate. However, rarely these site-selective approaches have been applied to immobilize enzymes on nanoparticles. In this review, for the first time, we illustrate how to adapt site-directed chemical modification (SDCM) methods for immobilizing enzymes on iron-based MNP. These strategies are mainly chemical but may additionally require genetic and enzymatic methods. We critically examine each method and evaluate their scope for simple, quick, efficient, mild and economical immobilization of enzymes on MNP. The improvements in the catalytic properties of few available examples of immobilized enzymes are also discussed. We conclude the review with the applications and future prospects of site-selectively modified magnetic enzymes and potential benefits of this technology in improving enzymes, including cold-adapted homologues, modular enzymes, and CO2-sequestering, as well as non-iron based nanomaterials.


Assuntos
Biotecnologia/métodos , Enzimas Imobilizadas/química , Nanopartículas de Magnetita/química , Sequestrantes/química , Dióxido de Carbono/química , Catálise , Domínio Catalítico , Enzimas Imobilizadas/genética , Ferro/química , Especificidade por Substrato
6.
Ren Fail ; 41(1): 47-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30732506

RESUMO

AST-120 (KREMEZIN®) consists of oral, spherical carbon particles that adsorb uremic toxins and their precursors within the gastrointestinal tract, allowing them to be excreted in the feces. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate are abundant in the blood of chronic kidney disease (CKD) patients and are related to the progression of both CKD and cardiovascular disease. AST-120 was approved in Japan in 1991 followed by Korea (2004), Taiwan (2007) and the Philippines (2010) for treating uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive CKD. In this review, we provide an overview of the past clinical data on AST-120 from 1982 to 2013. The effect of AST-120 for renal events was not supported in the primary analysis of randomized clinical trials. However, post-hoc analyses revealed significant differences between the AST-120 and control groups in the second Japanese phase III trial and in the multinational Evaluating Prevention of Progression in CKD (EPPIC) trials. Furthermore, inhibitory effects on the progression of CKD, as represented by amelioration in the estimated glomerular filtration rate (eGFR) decline and serum creatinine (sCr) elevation were suggested. These results suggest that AST-120 delays the decline in renal function. In addition, AST-120 may prolong the time to the initiation of dialysis, especially in patients with progressive CKD. For further verification of the clinical efficacy of AST-120, future study inclusion criteria should be determined carefully, defining progressive CKD using markers such as declines in eGFR and sCr elevation.


Assuntos
Carbono/uso terapêutico , Óxidos/uso terapêutico , Insuficiência Renal Crônica/terapia , Sequestrantes/uso terapêutico , Toxinas Biológicas/toxicidade , Uremia/terapia , Adsorção , Biomarcadores/análise , Carbono/farmacologia , Creatinina/sangue , Progressão da Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Rim/fisiopatologia , Óxidos/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sequestrantes/farmacologia , Fatores de Tempo , Toxinas Biológicas/química , Resultado do Tratamento , Uremia/sangue , Uremia/fisiopatologia
7.
Toxins (Basel) ; 10(12)2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30567330

RESUMO

The study applied ¹H NMR-based plasma metabolomics to identify candidate biomarkers of aflatoxin B1 (AFB1) ingestion in dairy cows fed no sequestering agents and evaluate the effect of supplementing clay and/or a Saccharomyces cerevisiae fermentation product (SCFP) on such biomarkers. Eight lactating cows were randomly assigned to 1 of 4 treatments in a balanced 4 × 4 Latin square design with 2 squares. Treatments were: control, toxin (T; 1725 µg AFB1/head/day), T with clay (CL; 200 g/head/day), and CL with SCFP (CL + SCFP; 35 g of SCFP/head/day). Cows in T, CL, and CL + SCFP were dosed with AFB1 from d 26 to 30. The sequestering agents were top-dressed from d 1 to 33. On d 30 of each period, 15 mL of blood was taken from the coccygeal vessels and plasma samples were prepared by centrifugation. Compared to the control, T decreased plasma concentrations of alanine, acetic acid, leucine, arginine and valine. In contrast, T increased plasma ethanol concentration 3.56-fold compared to control. Treatment with CL tended to reduce sarcosine concentration, whereas treatment with CL + SCFP increased concentrations of mannose and 12 amino acids. Based on size of the area under the curve (AUC) of receiver operating characteristic and fold change (FC) analyses, ethanol was the most significantly altered metabolite in T (AUC = 0.88; FC = 3.56); hence, it was chosen as the candidate biomarker of aflatoxin ingestion in dairy cows fed no sequestering agent.


Assuntos
Aflatoxina B1/farmacologia , Argila , Etanol/sangue , Saccharomyces cerevisiae , Sequestrantes/farmacologia , Ração Animal , Animais , Biomarcadores/sangue , Bovinos , Dieta/veterinária , Ingestão de Alimentos , Feminino , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética
8.
AAPS PharmSciTech ; 19(6): 2710-2718, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29978292

RESUMO

Cyclodextrins are cyclic carbohydrates widely used as complexing and non-complexing excipients in drug delivery systems. The purpose of this work was to study the ability of hydroxypropyl-ß-cyclodextrin and ß-cyclodextrin to act as tablet fillers for direct compression. In this way, several parameters of the cyclodextrins were evaluated, namely: (i) the flow properties such as angle of repose, flow time, Carr index, and Hausner ratio; (ii) the compaction behavior, specifically the energies and forces exerted during tableting, the plasticity index, the lubrication efficiency, and compression profiles (force/time and work/displacement of the upper punch); and (iii) the influence on carbamazepine release characteristics from uncoated tablets, i.e., dissolution rate and disintegration time. In addition, these properties of the cyclodextrins were compared with those from other commonly used direct compression fillers (lactose monohydrate, mannitol, calcium hydrogen phosphate dihydrate, and microcrystalline cellulose) and co-processed excipients (microcrystalline cellulose/mannitol and lactose monohydrate/cellulose). Three main conclusions can be drawn: (i) the studied cyclodextrins can be used as tablet fillers for direct compression; (ii) hydroxypropyl-ß-cyclodextrin showed better properties than ß-cyclodextrin mainly at the level of the physics of compression (higher values of plasticity index and lubrication efficiency) and of the drug release characteristics (faster and greater dissolution rate and a shorter disintegration time); and (iii) lactose monohydrate and hydroxypropyl-ß-cyclodextrin displayed the best results. As there are people intolerant to lactose, hydroxypropyl-ß-cyclodextrin, although its cost is higher, can be considered a good substitute for lactose.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Química Farmacêutica/métodos , Força Compressiva , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Excipientes/química , Excipientes/metabolismo , Pressão , Sequestrantes/química , Sequestrantes/metabolismo , Solubilidade , Comprimidos , beta-Ciclodextrinas/metabolismo
9.
Int J Neuropsychopharmacol ; 21(7): 697-704, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982443

RESUMO

Background: Drug-induced alterations in gene expression play an important role in the development of addictive behavior. Numerous transcription factors have been implicated in mediating the gene expression changes that occur in drug addiction. Nuclear factor kappa B is an inducible transcription factor complex that is rapidly activated by diverse stimuli. Methods: We performed next-generation high-throughput sequencing of the prefrontal cortex in a mouse model of repeated cocaine administration combined with pharmacological nuclear factor kappa B inhibition to identify nuclear factor kappa B target genes that participate in the cocaine addiction process. Results: We found that the nuclear factor kappa B antagonist sodium diethyldithiocarbamate trihydrate significantly reversed the cocaine-induced expression changes of the amphetamine addiction pathway. Genes that demonstrated differential expression in response to cocaine treatment that was also reversed by sodium diethyldithiocarbamate trihydrate were enriched for the axon guidance pathway. Furthermore, the nuclear factor kappa B homo-dimer motif could be mapped to 86 of these sodium diethyldithiocarbamate trihydrate-reversed genes, which were also enriched for axon guidance. Conclusions: We suggest that nuclear factor kappa B directly modifies the expression of axon guidance pathway members, leading to cocaine sensitization. Our findings reveal the role of prefrontal cortex nuclear factor kappa B activity in addiction and uncover the molecular mechanisms by which nuclear factor kappa B drives changes in the addicted brain.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , NF-kappa B/genética , Córtex Pré-Frontal/metabolismo , Sequenciamento Completo do Exoma/métodos , Animais , Comportamento Animal , Modelos Animais de Doenças , Ditiocarb/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , Sequestrantes/farmacologia
10.
Free Radic Res ; 52(8): 896-906, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30035649

RESUMO

Reactive carbonyl species (RCS) are cytotoxic molecules that originate from lipid peroxidation and sugar oxidation. Natural derivatives can be an attractive source of potential RCS scavenger. However, the lack of analytical methods to screen and identify bioactive compounds contained in complex matrices has hindered their identification. The sequestering actions of various rice extracts on RCS have been determined using ubiquitin and 4-hydroxy-2-nonenal (HNE) as a protein and RCS model, respectively. Black rice with giant embryo extract was found to be the most effective among various rice varieties. The identification of bioactive compounds was then carried out by an isotopic signature profile method using the characteristic isotopic ion cluster generated by the mixture of HNE: 2H5-HNE mixed at a 1:1 stoichiometric ratio. An in-house database was used to obtain the structures of the possible bioactive components. The identified compounds were further confirmed as HNE sequestering agents through HPLC-UV analysis.


Assuntos
Antocianinas/química , Espectrometria de Massas/métodos , Oryza/química , Extratos Vegetais/química , Sequestrantes/metabolismo , Antocianinas/análise
11.
Food Chem ; 262: 78-85, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29751925

RESUMO

Triterpene glycosides namely momordicoside K and momordicoside L causes bitterness in bitter-gourd thereby reducing its consumer acceptance. Reducing bitterness of the juice by addition of ß-cyclodextrin (0.25-2%) was attempted and its effect on sensory quality, total phenolic content, antioxidant activity and antidiabetic potential was evaluated. Juice with 1.5% ß-cyclodextrin demonstrated highest score (7.7 ±â€¯0.3) for sensory acceptability compared to the control (3.8 ±â€¯0.7). A significantly (p < 0.05) higher total phenolic content and antioxidant activity was observed. A marginal (10%) but significant (p < 0.05) reduction in α-glucosidase inhibition activity without affecting α-amylase activity was noted. Results from NMR, ROESY and FTIR studies indicated formation of an inclusion complex by interaction of hydrophobic triterpenoidal region of momordicosides with ß-cyclodextrin.


Assuntos
Sucos de Frutas e Vegetais/análise , Hipoglicemiantes/análise , Momordica charantia/química , Saponinas/química , Paladar , beta-Ciclodextrinas/química , Antioxidantes/análise , Feminino , Humanos , Hipoglicemiantes/farmacologia , Masculino , Fenóis/análise , Sequestrantes/química
12.
AAPS PharmSciTech ; 19(5): 2255-2263, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29748896

RESUMO

Norfloxacin, an antibiotic that exists in different solid forms, has very unfavorable properties in terms of solubility and stability. Binary complexes of norfloxacin, in the solid form C, and ß-cyclodextrin were procured by the kneading method and physical mixture. Their effect on the solubility, the dissolution rate, and the chemical and physical stability of norfloxacin was evaluated. To perform stability studies, the solid samples were stored under accelerated storage conditions, for a period of 6 months. Physical stability was monitored through powder X-ray diffraction, high-resolution 13C solid-state nuclear magnetic resonance, and scanning electron microscopy. The results showed evidence that the kneaded complex increased and modulated the dissolution rate of norfloxacin C. Furthermore, it was demonstrated that the photochemical stability was increased in the complex, without affecting its physical stability. The results point to the conclusion that the new kneading complex of norfloxacin constitutes an alternative tool to formulate a potential oral drug delivery system with improve oral bioavailability.


Assuntos
Antibacterianos/química , Antibacterianos/metabolismo , Norfloxacino/química , Norfloxacino/metabolismo , beta-Ciclodextrinas/química , beta-Ciclodextrinas/metabolismo , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Sequestrantes/química , Sequestrantes/metabolismo , Solubilidade , Difração de Raios X
13.
Curr Gastroenterol Rep ; 20(3): 10, 2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29582208

RESUMO

PURPOSE OF REVIEW: To provide an update on the prevalence, pathophysiology, disease associations, and treatment options for bile acid malabsorption (BAM). RECENT FINDINGS: •Molecular mechanisms-BAs prevent water reabsorption and increase water secretion by intracellular mediators, increasing aquaporin channels and intracellular permeability. •Inflammatory bowel disease-new molecular mechanisms of BAM are identified in patients without ileal disease, including changes in expression of ileal BA transporter and nuclear receptors involved in BA homeostasis. •Microscopic colitis-BAM is one of the mechanisms leading to microscopic colitis. •Diagnostic testing-new diagnostic tests have been launched in the USA (serum C4 and fecal 48-h BA excretion); stimulated FGF19 has higher detection of BAM compared to fasting sample alone. •Treatment-investigational FXR agonists may provide a daily, oral option for treatment of BAM instead of BA sequestrants. There is a greater appreciation of the biological role of bile acids across multiple fields of medicine, including gastrointestinal indications.


Assuntos
Ácidos e Sais Biliares/metabolismo , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/terapia , Ácidos e Sais Biliares/fisiologia , Biomarcadores/sangue , Colecistectomia/efeitos adversos , Diarreia/etiologia , Diarreia/fisiopatologia , Fezes/química , Humanos , Doenças Inflamatórias Intestinais/complicações , Síndromes de Malabsorção/epidemiologia , Síndromes de Malabsorção/fisiopatologia , Lesões por Radiação/etiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Sequestrantes/uso terapêutico , Esteatorreia/etiologia , Esteatorreia/fisiopatologia , Ácido Taurocólico/análogos & derivados
14.
Ann Med ; 50(4): 303-311, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29578362

RESUMO

Hypercholesterolemia is a pathological condition which has been reported in 39% of the worlds' adult population. We aimed to review molecular aspects of current and novel therapeutic approaches based on low-density lipoprotein cholesterol lowering strategies. Pathogenic mutations in the LDLR, ApoB, PCSK9 and LDLRAP genes cause deficient clearance of circulating low-density lipoprotein cholesterol particles via hepatic LDL receptor. This leads to increased plasma LDL cholesterol levels from birth, which can cause LDL depositions in the arterial walls. Ultimately, it progresses to atherosclerosis and an increased risk of premature cardiovascular diseases. Currently, statins, Ezetimibe, Bile acid sequestrants and PCSK9 inhibitors are the main therapeutic agents for the treatment of hypercholesterolemia. Moreover, novel RNA-based therapy had a strong impact on therapeutic strategies in recent decades. Additional development in understanding of the molecular basis of hypercholesterolemia will provide opportunities for the development of targeted therapy in the near future. Key Messages The most common genes involved in hypercholesterolemia are LDLR, PCSK9 and ApoB. Pharmacogenetic effects are typically constrained to pathways closely related to the pharmacodynamics and pharmacokinetics. Change in lifestyle and diet along with treatment of the underlying disease and drug therapy are the current therapeutic strategies.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Terapia Genética/métodos , Hipercolesterolemia/terapia , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Anticolesterolemiantes/farmacologia , Aterosclerose/sangue , Ácidos e Sais Biliares/antagonistas & inibidores , Ácidos e Sais Biliares/metabolismo , LDL-Colesterol/metabolismo , Progressão da Doença , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , MicroRNAs/genética , MicroRNAs/uso terapêutico , Mutação , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sequestrantes/farmacologia , Sequestrantes/uso terapêutico
15.
Diabetes Obes Metab ; 20(7): 1623-1631, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29493868

RESUMO

AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. MATERIALS AND METHODS: In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. RESULTS: Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. CONCLUSIONS: Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.


Assuntos
Glicemia/metabolismo , Quelantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Sevelamer/uso terapêutico , Idoso , Área Sob a Curva , Ácidos e Sais Biliares/metabolismo , Peptídeo C/metabolismo , Colecistocinina/metabolismo , Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Metabolismo Energético , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Esvaziamento Gástrico , Polipeptídeo Inibidor Gástrico/metabolismo , Microbioma Gastrointestinal/genética , Glucagon/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Sequestrantes/uso terapêutico , Triglicerídeos/metabolismo
16.
Pharm Dev Technol ; 23(10): 986-997, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27808002

RESUMO

Levodopa is a promising candidate for administration via the transdermal route because it exhibits a short plasma half-life and has a small window of absorption in the upper section of the small intestine. The aim of this study was to prepare stable levodopa transdermal patches. Both xanthan gum and Carbopol 971 polymers were selected with ethylcellulose constituting the backing layer of the prepared patches. The effect of adding ß-cyclodextrin on the prepared patches was investigated. The uniformity in thickness, weight and content of the studied patches was acceptable. Physicochemical characterization revealed that there was no interaction between levodopa and the applied polymer. The results proved that levodopa precipitated as an amorphous form in carbopol patches. Controlled drug release was achieved for all the tested patches over a 6 h period. However, increased permeation was achieved for the carbopol patches. Although cyclodextrin did not enhance levodopa permeation, the stability study confirmed that levodopa stability was enhanced when complexed with ß-cyclodextrin. The cumulative amount of drug released from carbopol patches is slightly higher than that of xanthan patches. The optimal stability was achieved in the carbopol/levodopa:ß-cyclodextrin patch. The levodopa-ß-cyclodextrin complex was successfully characterized using X-ray diffraction, NMR analysis and molecular dynamics simulations. In conclusion, carbopol/levodopa:ß-cyclodextrin patches can be considered as a promising stable and effective transdermal drug-delivery system.


Assuntos
Antiparkinsonianos/química , Levodopa/química , Adesivo Transdérmico , beta-Ciclodextrinas/química , Acrilatos/administração & dosagem , Acrilatos/química , Acrilatos/metabolismo , Administração Cutânea , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/metabolismo , Cristalografia por Raios X/métodos , Combinação de Medicamentos , Estabilidade de Medicamentos , Levodopa/administração & dosagem , Levodopa/metabolismo , Masculino , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/metabolismo , Ratos , Ratos Sprague-Dawley , Sequestrantes/administração & dosagem , Sequestrantes/química , Sequestrantes/metabolismo , Difração de Raios X/métodos , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/metabolismo
17.
Expert Rev Clin Pharmacol ; 10(12): 1403-1407, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29064296

RESUMO

BACKGROUND: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide' s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6-8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations - such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies. METHODS: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days. RESULTS AND CONCLUSIONS: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.


Assuntos
Resinas de Troca de Ânions/farmacologia , Colestipol/farmacologia , Crotonatos/farmacocinética , Sequestrantes/farmacologia , Toluidinas/farmacocinética , Adolescente , Adulto , Resinas de Troca de Ânions/administração & dosagem , Resinas de Troca de Ânions/efeitos adversos , Resina de Colestiramina/administração & dosagem , Resina de Colestiramina/efeitos adversos , Resina de Colestiramina/farmacologia , Colestipol/administração & dosagem , Colestipol/efeitos adversos , Crotonatos/administração & dosagem , Feminino , Humanos , Masculino , Sequestrantes/administração & dosagem , Sequestrantes/efeitos adversos , Toluidinas/administração & dosagem , Resultado do Tratamento , Adulto Jovem
18.
J Am Coll Cardiol ; 70(14): 1785-1822, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28886926

RESUMO

In 2016, the American College of Cardiology published the first expert consensus decision pathway (ECDP) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk. Since the publication of that document, additional evidence and perspectives have emerged from randomized clinical trials and other sources, particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in secondary prevention of ASCVD. Most notably, the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial and SPIRE-1 and -2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), assessing evolocumab and bococizumab, respectively, have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients. In addition, further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published. Based on results from these important analyses, the ECDP writing committee judged that it would be desirable to provide a focused update to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities. In the following summary table, changes from the 2016 ECDP to the 2017 ECDP Focused Update are highlighted, and a brief rationale is provided. The content of the full document has been changed accordingly, with more extensive and detailed guidance regarding decision making provided both in the text and in the updated algorithms. Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities on statin therapy for secondary prevention. The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C <190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes. Based on feedback and further deliberation, the ECDP writing committee down-graded recommendations regarding bile acid sequestrant use, recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe. For clarification, the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia, based on clinical criteria with and without genetic testing. Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians, unless there was a compelling reason or new evidence, in which case justification is provided.


Assuntos
Anticolesterolemiantes/farmacologia , Cardiologia/métodos , Doença da Artéria Coronariana/prevenção & controle , Ezetimiba/farmacologia , Hipercolesterolemia/tratamento farmacológico , Conduta do Tratamento Medicamentoso/organização & administração , Quimioprevenção/métodos , LDL-Colesterol/análise , Consenso , Inibidores Enzimáticos/farmacologia , Humanos , Hipercolesterolemia/diagnóstico , Sequestrantes/farmacologia , Estados Unidos
19.
Chembiochem ; 18(16): 1583-1588, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28586110

RESUMO

We measured the affinity of five molecular container compounds (calabadions 1 and 2, CB[7], sulfocalix[4]arene, and HP-ß-CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods (1 H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (Ka values) spanning from <102 to >108 m-1 . We also report X-ray crystal structures of CB[7]⋅methamphetamine and 1⋅methamphetamine. We found that 2, but not CB[7], was able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The bioavailability of the calabadions and their convergent building block synthesis suggest potential for further structural optimization as reversal agents for intoxication with nonopioid drugs of abuse for which no treatments are currently available.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Drogas Ilícitas/toxicidade , Locomoção/efeitos dos fármacos , Metanfetamina/toxicidade , Sequestrantes/farmacologia , Ácidos Sulfônicos/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Cristalografia por Raios X , Fentanila/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Drogas Ilícitas/química , Imidazóis/química , Imidazóis/farmacologia , Masculino , Metanfetamina/química , Fenóis/química , Fenóis/farmacologia , Ratos Sprague-Dawley , Sequestrantes/química , Ácidos Sulfônicos/química
20.
Arch Pathol Lab Med ; 141(9): 1276-1282, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28169559

RESUMO

CONTEXT: - Medication resins, including Kayexalate, sevelamer, and bile acid sequestrants, can be encountered in gastrointestinal tract specimens. Their classic histologic appearances have been well documented, but pathologist recognition of the resins is 75%, patient history is not always available, and atypical morphologic findings are sometimes present. OBJECTIVE: - To offer a succinct overview of resins in the gastrointestinal tract, including typical and atypical appearances, in order to serve as a quick reference guide. DATA SOURCES: - The study comprises published literature, survey data, and our personal experiences. CONCLUSIONS: - Classic morphology is the benchmark for identifying these resins, but color, location, and fish scale pattern can deviate from the norm, making proper identification a challenge. Patient history should be sought whenever possible, and ancillary staining is an option when necessary. Additionally, the presence of resins should prompt the pathologist to search for potentially related diagnoses (namely, causes of diarrhea in patients on bile acid sequestrants and diagnoses associated with renal failure in patients on Kayexalate or sevelamer).


Assuntos
Resinas de Troca de Cátion/efeitos adversos , Trato Gastrointestinal/patologia , Humanos , Patologia Cirúrgica/métodos , Poliestirenos/efeitos adversos , Sequestrantes/efeitos adversos , Sevelamer/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA