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1.
Eur J Pharm Biopharm ; 142: 387-395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306752

RESUMO

Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.


Assuntos
Excipientes/química , Jejum/metabolismo , Absorção Intestinal/efeitos dos fármacos , Jejuno/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Líquidos Corporais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Dodecilsulfato de Sódio/química , Solubilidade/efeitos dos fármacos
2.
Res Vet Sci ; 125: 309-314, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31351201

RESUMO

Vilazodone (VLZ) is a drug approved for the treatment of major depressive disorder in humans but no data are available for dogs. The present study aimed to evaluate the pharmacokinetics of a single oral 40 mg dose of VLZ in healthy Labrador dogs (n = 6) in fasted and fed conditions. Dogs were randomly divided in two (n = 3) groups in a cross-over study design (2 × 2). Group I was administered with VLZ at 40 mg/dog after fasting over-night. Group II was fed prior to and after administration of the same dose. A two-week wash-out period was observed. Plasma samples collected underwent LC-MS/MS analysis. VLZ concentrations were quantified in dogs' plasma in two different windows of time: 30 min to 10 h for the fasted group and 4 h to 35 h for the fed group. The values for t1/2λz were statistically different between the groups (fed, 4.6 ±â€¯1.1 h vs fasted, 1.7 ±â€¯0.2 h). Tmax drastically changed between the groups (fed, 10 h vs fasted, 1.5 h), while Cmax did not significantly vary (fed, 39.4 ±â€¯5.6 ng/mL vs fasted, 38.7 ±â€¯4.8 ng/mL). The AUC value was always statistically higher in the fed group. As a result, the average relative oral fasted bioavailability of VLZ was low, 28.8 ±â€¯6.1%. In conclusion, feeding can affect the pharmacokinetics of VLZ in the dog.


Assuntos
Antidepressivos/farmacocinética , Cães/metabolismo , Jejum/metabolismo , Cloridrato de Vilazodona/farmacocinética , Animais , Cromatografia Líquida , Estudos Cross-Over , Feminino , Masculino , Distribuição Aleatória , Espectrometria de Massas em Tandem
3.
PLoS Genet ; 15(6): e1008242, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31246952

RESUMO

Low oxygen conditions (hypoxia) can impair essential physiological processes and cause cellular damage and death. We have shown that specific hypoxic conditions disrupt protein homeostasis in C. elegans, leading to protein aggregation and proteotoxicity. Here, we show that nutritional cues regulate this effect of hypoxia on proteostasis. Animals fasted prior to hypoxic exposure develop dramatically fewer polyglutamine protein aggregates compared to their fed counterparts, indicating that the effect of hypoxia is abrogated. Fasting also reduced the hypoxia-induced exaggeration of proteostasis defects in animals that express Aß1-42 and in animals with a temperature-sensitive mutation in dyn-1, suggesting that this effect was not specific to polyglutamine proteins. Our data also demonstrate that the nutritional environment experienced at the onset of hypoxia dictates at least some aspects of the physiological response to hypoxia. We further demonstrate that the insulin/IGF-like signaling pathway plays a role in mediating the protective effects of fasting in hypoxia. Animals with mutations in daf-2, the C. elegans insulin-like receptor, display wild-type levels of hypoxia-induced protein aggregation upon exposure to hypoxia when fed, but are not protected by fasting. DAF-2 acts independently of the FOXO transcription factor, DAF-16, to mediate the protective effects of fasting. These results suggest a non-canonical role for the insulin/IGF-like signaling pathway in coordinating the effects of hypoxia and nutritional state on proteostasis.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Fator de Crescimento Insulin-Like I/genética , Insulina/genética , Receptor de Insulina/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Jejum/metabolismo , Regulação da Expressão Gênica/genética , Hipóxia/genética , Hipóxia/metabolismo , Mutação/genética , Peptídeos/genética , Transdução de Sinais/genética
4.
Eur J Pharm Biopharm ; 141: 191-209, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150808

RESUMO

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.


Assuntos
Danazol/farmacocinética , Jejum/metabolismo , Mucosa Intestinal/metabolismo , Administração Oral , Animais , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Química Farmacêutica/métodos , Cães , Excipientes/química , Absorção Intestinal/efeitos dos fármacos , Intestinos , Modelos Biológicos , Permeabilidade/efeitos dos fármacos , Fenômenos Físicos , Solubilidade/efeitos dos fármacos
5.
Diabetes Res Clin Pract ; 153: 145-149, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31108138

RESUMO

AIMS: Depression in diabetes has been associated with hyperglycemia and an increase risk for metabolic disorder complications. Ramadan is a period of self-discipline, self control, and spirituality, which has shown benefits in physical, mental, and social well being. The aim of this study is to examine the association between fasting during the month of Ramadan and depression. METHODS: Data from 463 participants were collected at three time points. A paired t-test was used to examine the difference between PHQ-9 score and difference of PAID score before and after Ramadan to measure depression. A multivariable regression with adjusting for potential confounders was used to study the association between fasting and depression. RESULTS: The difference in PHQ-9 score before and after Ramadan was -3.5 points (95% Confidence Interval (CI) -4.05 to -2.95). The difference in PAID score before and after the Ramadan was -5.02 points (95% CI -6.38 to -3.69). For every one year increase in diabetes diagnosis PHQ-9 score decreased by 0.09 (95% CI -0.17 to 0.003) after Ramadan. Female participants had 1.17 more points (95% CI -0.23 to 0.02) decrease in PHQ-9 score compared to male participants. CONCLUSION: Improving depression in people with diabetes is crucial in controlling blood glucose and metabolic disorder complications in people with diabetes. People with diabetes who experience depression may improve their depression by increasing self discipline, self control, and manage disease.


Assuntos
Depressão/psicologia , Diabetes Mellitus Tipo 2/sangue , Jejum/metabolismo , Hipoglicemia/etiologia , Feminino , Humanos , Islamismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
6.
Artigo em Inglês | MEDLINE | ID: mdl-31028911

RESUMO

Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including CIDEA, CIDEB and CIDEC, play an important role in energy metabolism. In the present study, CIDEA, CIDEB and CIDEC cDNAs were firstly isolated and characterized from grass carp Ctenopharyngodon idella, encoding peptides of 205, 208 and 238 amino acids, respectively. Analysis of the exon-intron structures clarified that grass carp CIDEA, CIDEB and CIDEC consisted of 5 coding exons, 5 coding exons and 6 coding exons, respectively, which is similar with human and mouse. Both CIDE family genes mRNAs were expressed in a wide range of tissues, but the abundance of each CIDE family gene mRNA showed the tissue-dependent expression patterns. Time-course analysis of CIDE family expressions indicated that their expression were enhanced significantly from day 0 to day 8 after differentiation. Forskolin caused an increase in CIDEA and CIDEC expression, and the effects were attenuated by treatment with CREB inhibitor, revealing that CIDEA and CIDEC are regulated by CREB. Further study found that CIDEA and CIDEC mRNA levels did not show significant changes during fasting. These results provide the groundwork to elucidate the gene structure and physiological function of CIDE family in fish.


Assuntos
Adipócitos/metabolismo , Proteínas Reguladoras de Apoptose , Carpas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Jejum/metabolismo , Proteínas de Peixes , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Carpas/genética , Carpas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
7.
Exp Anim ; 68(3): 371-380, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30944267

RESUMO

Ketogenic diet (KD) has been used in epilepsy for decades, but previous studies found it may cause severe bone loss. Every-other-day ketogenic diet (EODKD), the combination of KD with intermittent fasting, showed better potential for seizure control recently, while its effects on bone remain unknown. This study aims to establish different ketogenic rat models and compare the influence of EODKD with KD on bone microstructure and metabolism. Thirty male Sprague-Dawley rats were divided into Control, KD and EODKD groups, fed with standard diet, continuous and intermittent ketogenic diet respectively. After 12 weeks, bone mineral density (BMD) and body fat percentage were obtained by dual energy X-ray absorptiometry. Micro-CT and three-point bending test were used to evaluate the bone microstructure and mechanical properties. Activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) were measured, together with the osteogenic capabilities of bone marrow stromal cells (BMSCs) tested by ALP activities and alizarin red stain in different osteogenic stage. Both EODKD and KD induced higher ketone and more fat percentage, but led to lower body weight compared with Control group. They both compromised bone mass and mechanical properties. Compared with KD, EODKD demonstrated higher ketone levels, but it also inhibited osteoclastic process as well as early osteogenic differentiation. In general, EODKD accelerated ketosis, but may not deteriorate bone microstructure and strength than KD.


Assuntos
Densidade Óssea/fisiologia , Dieta Cetogênica , Jejum/metabolismo , Células-Tronco Mesenquimais/fisiologia , Osteogênese , Ratos/fisiologia , Absorciometria de Fóton , Animais , Modelos Animais de Doenças , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley , Microtomografia por Raio-X
8.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995792

RESUMO

The liver is the central organ of glycolipid metabolism, which regulates the metabolism of lipids and glucose to maintain energy homeostasis upon alterations of physiological conditions. Researchers formerly focused on the phosphorylation of glucagon in controlling liver metabolism. Noteworthily, emerging evidence has shown glucagon could additionally induce acetylation to control hepatic metabolism in response to different physiological states. Through inducing acetylation of complex metabolic networks, glucagon interacts extensively with various energy-sensing factors in shifting from glucose metabolism to lipid metabolism during prolonged fasting. In addition, glucagon-induced acetylation of different energy-sensing factors is involved in the advancement of nonalcoholic fatty liver disease (NAFLD) to liver cancer. Here, we summarize the latest findings on glucagon to control hepatic metabolism by inducing acetylation of energy-sensing factors. Finally, we summarize and discuss the potential impact of glucagon on the treatment of liver diseases.


Assuntos
Glucagon/metabolismo , Fígado/metabolismo , Acetilação , Animais , Metabolismo Energético , Jejum/metabolismo , Glucose/metabolismo , Homeostase , Humanos , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
9.
Acta Haematol ; 141(3): 189-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840964

RESUMO

Calorie restriction (CR) has been studied as a way to prolong longevity, and CR before chemotherapy can reduce hematological toxicity in cancer patients. We investigated the influence of fasting on immune cells and immature hematopoietic cells. In fasted mice, there was a significant reduction in the hematopoietic stem cell count but no significant difference for progenitor cells. Colony assays showed no difference and the rates of early and late apoptosis were almost identical when comparing fasted and control mice. DNA cell cycle analysis of immature bone marrow (BM) cells showed that CR caused a significant increase in the percentage in the G0/G1 phase and decreases in the S and G2/M phases. We detected a remarkable increase of T cells in the BM of fasted mice. CD44- naïve CD8+ T cells were more numerous in fasted BM, as were naïve CD4+ T cells, and part of those T cells showed less tendency in the G0/G1 phase. Immature hematopoietic cells remained in a relatively quiescent state and retention of colony-forming capacity during CR. The number of naïve T cells in the BM of fasted mice increased. These findings imply immature hematopoietic cells and some lymphoid cells can survive starvation, whilst maintaining their function.


Assuntos
Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Jejum/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Células-Tronco Hematopoéticas/citologia , Camundongos
10.
Biopharm Drug Dispos ; 40(3-4): 121-134, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30891805

RESUMO

BACKGROUND: Food may affect the oral absorption of drugs. PURPOSE: The aim of the present study was to investigate the influence of food on the oral absorption of clarithromycin by evaluating the effect of media parameters, such as pH, bile secretions and food composition, on the release of the drug from immediate release tablets, using in vitro and in silico assessments. METHOD: The solubility, disintegration and dissolution profiles of clarithromycin 500 mg immediate release tablets in compendial media with/without the addition of a homogenized FDA meal as well as in biorelevant simulated intestinal media mimicking fasting and fed conditions were determined. These in vitro data were input to GastroPlus™, which was used for developing a physiological absorption model capable of anticipating the effect of food on clarithromycin absorption. Level A in vitro-in vivo linear correlations were established using a mechanistic absorption modelling based deconvolution approach. RESULTS: The pH of the media has a profound effect on clarithromycin solubility, tablet disintegration and drug release. Clarithromycin has lower solubility in biorelevant media compared with other media, due to complex formation with bile salts. Clarithromycin tablets exhibited prolonged disintegration times and reduced dissolution rates in the presence of the standard FDA meal. The simulation model predicted no significant food effect on the oral bioavailability of clarithromycin. The developed IVIVC model considered SIF, acetate buffer and FaSSIF media to be the most relevant from the physiological standpoint. CONCLUSION: The intake of a standard FDA meal may have no significant effect on the oral bioavailability of clarithromycin immediate release tablet.


Assuntos
Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Interações Alimento-Droga , Modelos Biológicos , Administração Oral , Antibacterianos/administração & dosagem , Antibacterianos/química , Claritromicina/administração & dosagem , Claritromicina/química , Simulação por Computador , Liberação Controlada de Fármacos , Jejum/metabolismo , Suco Gástrico/química , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Secreções Intestinais/química , Solubilidade , Comprimidos
11.
Eur J Pharm Sci ; 132: 44-54, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30822502

RESUMO

Intestinal drug absorption following oral administration can be influenced by regional conditions (absorbing surface area, bacterial flora, motility, pH, mucus thickness) and food intake, all of which affect drug solubility and permeability. Therefore, it is crucial to assess the impact of these conditions on the drugability of drugs and formulations. In this study, the ability of the liposome-based mucus-PVPA in vitro permeability model to handle relevant intestinal pH conditions was evaluated, together with the investigation on the pH-dependent solubility and permeability profiles of five model drugs. This study additionally evaluated the impact of all commercially available versions of the fasted and fed state simulated intestinal fluids (SIFs) on the integrity of the barriers, and the permeabilities of one hydrophilic and one lipophilic compound were examined under these conditions. The model was found to be well-functioning in all tested pH conditions, and a pH-dependent trend was found for both solubility and permeability profiles for acidic and basic compounds, according to their degree of ionization. Moreover, the mucus layer and its pH-dependent viscosity particularly influenced the permeation of more lipophilic compounds. The PVPA barriers primarily maintained their functionality in the presence of the fed state SIFs, and the permeability of the two tested compounds showed to be influenced by their hydrophilicity/lipophilicity, their degree of interaction with mucus and by the bile salts and phospholipids content in the SIFs. Overall, the obtained results highlight the relevance of studying the effect that pH, mucus and SIFs have on intestinal drug absorption, and suggest the suitability of the mucus-PVPA model for such investigations.


Assuntos
Jejum/metabolismo , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Secreções Intestinais/metabolismo , Intestino Delgado/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Biomimética , Interações Alimento-Droga , Humanos , Membranas Artificiais , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Farmacocinética , Fosfolipídeos/química , Solubilidade
12.
BMC Physiol ; 19(1): 1, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30866899

RESUMO

BACKGROUND: Skeletal muscle prefers carbohydrate use to fatty acid (FA) use as exercise intensity increases. In contrast, skeletal muscle minimizes glucose use and relies more on FA during fasting. In mice deficient for FABP4 and FABP5 (double knockout (DKO) mice), FA utilization by red skeletal muscle and the heart is markedly reduced by the impairment of trans-endothelial FA transport, with an increase in glucose use to compensate for reduced FA uptake even during fasting. We attempted to determine whether prolonged fasting affects exercise performance in DKO mice, where constant glucose utilization occurs. RESULTS: A single bout of treadmill exercise was performed in the fed and fasted states. The initial speed was 10 m/min, and gradually increased by 5 m/min every 5 min up to 30 m/min until the mice stopped running. Running distance was significantly reduced by DKO genotype and prior fasting, leading to the shortest distance in fasted DKO mice. Levels of glycogen in skeletal muscle and the liver were nearly depleted in both WT and DKO mice during prolonged fasting prior to exercise. Levels of TG in skeletal muscle were not reduced by exercise in fasted DKO mice, suggesting that intramuscular TG was not utilized during exercise. Hypoglycaemia was accelerated in fasted DKO mice, and this acceleration could be due to constant glucose utilization by red skeletal muscle and the heart where FA uptake is diminished due to defective trans-endothelial FA transport. Taken together, energy supply from serum and storage in skeletal muscle were very low in fasted DKO mice, which could lead to a significant reduction in exercise performance. CONCLUSIONS: FABP4/5 have crucial roles in nutrient homeostasis during prolonged fasting for maintaining exercise endurance capacity.


Assuntos
Metabolismo Energético/fisiologia , Tolerância ao Exercício/fisiologia , Jejum/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Neoplasias/genética , Condicionamento Físico Animal/fisiologia , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Proteínas de Neoplasias/metabolismo
13.
Eur J Pharm Sci ; 131: 153-158, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30790704

RESUMO

The main objective of this study was to evaluate the pharmacokinetics of ritonavir (RTV) nanosuspension in rats in both fed and fasted state in comparison with coarse powder, physical mixture and commercial product (Norvir®). The point to point relation model was generated between the results of in vitro dissolution and in vivo pharmacokinetic studies. The oral RTV nanosuspension was prepared with microfluidization method. Nanosuspension was obtained with 540-550 nm of particle size, 0.1-0.4 of particle size distribution and about -20 mV of zeta potential values. According to in vivo pharmacokinetic studies in rats, Cmax and AUC0-t values in nanosuspension displayed an 8.9- and 12.5-fold increase compared to the coarse powder, and a 1.9- and 2.1-fold increase compared to the commercial product, respectively in the fed group. The point to point relation model showed that the correlation model was significant. It is concluded that nanosuspension is a promising drug delivery system to enhance oral bioavailability of ritonavir.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Nanopartículas/administração & dosagem , Ritonavir/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Jejum/metabolismo , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/química , Derivados da Hipromelose/química , Masculino , Nanopartículas/química , Ratos Wistar , Ritonavir/sangue , Ritonavir/química , Dodecilsulfato de Sódio/química , Suspensões
14.
Nutrients ; 11(2)2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678028

RESUMO

Intermittent fasting (IF) has been connected with health benefits such as weight loss, lower risk of coronary artery disease (CAD) and diabetes, increased longevity, and improved quality of life. However, the mechanisms of these IF benefits in humans require further investigation. This study sought to elucidate some of these mechanisms through secondary analyses of the Fasting and ExprEssion of Longevity Genes during fOOD abstinence (FEELGOOD) trial, in which apparently healthy participants were randomized in a Latin square design to a 24-h water-only fast and a 24-h ad libitum fed day. Two pathways were investigated, with trimethylamine N-oxide (TMAO) levels measured due to their association with elevated risk of CAD, along with conductance of a broad panel of metabolic analytes. Measurements were made at baseline, at the end of the fasting day, and at the end of the fed day. A fasting mean of 14.3 ng in TMAO was found versus the baseline mean of 27.1 ng with p = 0.019, although TMAO levels returned to baseline on refeeding. Further, acute alterations in levels of proline, tyrosine, galactitol, and urea plasma levels were observed along with changes in 24 other metabolites during the fasting period. These acute changes reveal short-term mechanisms which, with consistent repeated episodes of IF, may lead to improved health and reduced risk of CAD and diabetes.


Assuntos
Jejum/metabolismo , Jejum/fisiologia , Metaboloma/fisiologia , Metilaminas/sangue , Adulto , Idoso , Jejum/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Projetos Piloto
15.
AAPS PharmSciTech ; 20(2): 59, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30623248

RESUMO

Prediction of the effect of food on drug's pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state. Food can have various effects on drug dissolution and absorption, depending also on drug's properties. A physiologically based pharmacokinetic (PBPK) absorption model was built in GastroPlus™ to predict the food effect on generic and reference formulation and to predict the fed BE study outcome. During model development, we were searching for model inputs that impact and describe in vivo behavior of amorphous and crystalline forms of active pharmaceutical ingredient (API) in fast and fed conditions. The developed model was able to predict the food effect with up to 10% prediction error (PE). Performed virtual BE trials confirmed the BE of drug products in fed state. Our model was able to capture the difference between the two drug products containing different forms of API (amorphous and crystalline) and predict the food effect on both formulations.


Assuntos
Simulação por Computador , Desenvolvimento de Medicamentos/métodos , Jejum/metabolismo , Interações Alimento-Droga/fisiologia , Absorção Intestinal/fisiologia , Modelos Biológicos , Estudos Cross-Over , Cristalização , Composição de Medicamentos , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Solubilidade , Equivalência Terapêutica
16.
AAPS PharmSciTech ; 20(1): 37, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604142

RESUMO

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.


Assuntos
Jejum , Metilcelulose/análogos & derivados , Piperazinas/síntese química , Povidona/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Combinação de Medicamentos , Jejum/metabolismo , Metilcelulose/administração & dosagem , Metilcelulose/síntese química , Metilcelulose/metabolismo , Excipientes Farmacêuticos/administração & dosagem , Excipientes Farmacêuticos/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Povidona/administração & dosagem , Povidona/metabolismo , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Difração de Raios X/métodos
17.
Mol Med Rep ; 19(3): 1721-1727, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628688

RESUMO

Intermittent fasting (ImF) is known to reduce oxidative stress and affects adult neurogenesis in the hippocampal dentate gyrus. However, it is unknown how ImF affects endogenous antioxidants expressions, cell proliferation, and neuroblast differentiation and their dendrite remodeling over 3 months in the dentate gyrus of adult gerbils. The present study subjected 6­month old male gerbils to a normal diet or alternate­day ImF for 1, 2 and 3 months. Changes in body weight were not significantly different between gerbils fed a normal diet and on ImF. The present study also investigated the effects of ImF on antioxidant enzymes [superoxide dismutase (SOD)­1, SOD2 and catalase] using immunohistochemistry, and endogenous cell proliferation, neuroblast differentiation and neuroblast dendrite complexity by using Ki67 (a cell proliferation marker) and doublecortin (neuroblast differentiation marker) immunohistochemistry in the dentate gyrus. SOD1, SOD2 and CAT immunoreactivities were shown in cells in the granule cell and polymorphic layers. SOD1, SOD2 and catalase immunoreactivity in the cells peaked at 2, 1 and 1 month, respectively, following ImF. Cell proliferation was ~250, 129 and 186% of the control, at 1, 2 and 3 months of ImF, respectively. Neuroblast differentiation was ~41, 32 and 12% of the control, at 1, 2 and 3 months of ImF, respectively, indicating that dendrites of neuroblasts were more arborized and developed at 3 months of ImF. Taken together, these results indicate that ImF for 3 months improves endogenous SOD1, SOD2 and catalase expressions and enhances cell proliferation, and neuroblast dendrites complexity and maturation in the adult gerbil dentate gyrus.


Assuntos
Diferenciação Celular/genética , Dendritos/genética , Gerbillinae/genética , Neurogênese/genética , Animais , Antioxidantes/metabolismo , Catalase/genética , Proliferação de Células/genética , Dendritos/metabolismo , Giro Denteado/crescimento & desenvolvimento , Jejum/metabolismo , Gerbillinae/crescimento & desenvolvimento , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Humanos , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/genética , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética
19.
Nord J Psychiatry ; 73(2): 96-103, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30654674

RESUMO

BACKGROUND: Neurotrophin-3 (NTF3) and neurotrophin-4 (NTF4) play a crucial role in the neurodevelopment, differentiation, survival, and protection of neurons in different brain regions. Schizophrenia and depression are highly associated with metabolic abnormalities. Longitudinal and cross-sectional comparisons of NTF3 and NTF4 levels, as well as clinical and metabolic parameters, were studied in schizophrenia, first-episode depression, and control groups. MATERIALS AND METHODS: Serum NTF3 and NTF4 levels, body mass index (BMI), fasting serum glucose and lipid profile: cholesterol, triglyceride, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were measured at baseline and week 8 in 133 women: 55 patients with schizophrenia (19 with first-episode and 36 chronic), 30 patients with a first-episode depression and 48 healthy controls. The severity of the symptoms was evaluated with the Positive and Negative Syndrome Scale, 17-item Hamilton Depression Rating Scale and the Beck Depression Inventory. RESULTS: Longitudinal and cross-sectional comparisons did not detect any differences in the serum levels of NTF3 and NTF4 between studied groups. NTF3 and NTF4 levels were strongly correlated. Correlation of NTF3 and HDL-C levels at baseline was observed. Significant changes in cholesterol and fasting serum glucose levels in first-episode depression patients during 8 weeks of treatment were detected. Significant differences in BMI and LDL-C levels between schizophrenia and first-episode depression patients were discovered. CONCLUSIONS: To our knowledge, this is the first research which correlates NTF3 and NTF4 with metabolic parameters. Our study does not support the theory that the peripheral levels of NTF3 and NTF4 are disturbed in schizophrenia or first-episode depression.


Assuntos
Índice de Massa Corporal , Depressão/sangue , Fatores de Crescimento Neural/sangue , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Colesterol/sangue , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Jejum/metabolismo , Jejum/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Adulto Jovem
20.
Acta Diabetol ; 56(2): 219-226, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30637483

RESUMO

AIMS: In this study, we investigated whether adipose tissue insulin resistance (IR) is affected by the degree of obesity during the fasting and post-prandial state, independent of glucose tolerance among obese children and adolescents. We also tested whether systemic subclinical inflammation is associated with adipose tissue IR. METHODS: Subjects were recruited to the Yale Pathophysiology of Type 2 Diabetes in Youth Study (NCT01967849). An oral glucose-tolerance test was performed to establish glucose-tolerance status and blood samples were drawn for measurement of free fatty acids (FFAs), to calculate the area under the curve (AUC) of FFA. Adipose tissue insulin resistance was calculated as the product of insulin and FFA concentrations. RESULTS: In total, 671 children and adolescents (58.6% females) were included with a mean age of 13.3(2.7) years and BMI Z score of 2.45(0.31). The degree of obesity emerged as an independent predictor of both fasting and post-prandial adipose IR, p < 0.0001. Higher degree of obesity was associated with greater AUC FFA (lower suppression) compared to lower degree of obesity, p = 0.01. Furthermore, higher levels of IL-6 were positively associated with post-prandial adipose tissue IR, p = 0.02. CONCLUSIONS: The degree of obesity in childhood and adolescence is strongly associated with adipose tissue IR independent of glucose tolerance. This is reflected not only in calculated indices of adipose IR but also in lower suppression of FFAs during the OGTT regardless of glucose tolerance or fasting adipose tissue IR. Furthermore, markers of subclinical inflammation such as IL-6 are associated with adipose tissue IR, independent of other factors.


Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Resistência à Insulina/fisiologia , Obesidade Pediátrica , Adolescente , Área Sob a Curva , Índice de Massa Corporal , Criança , Estudos de Coortes , Correlação de Dados , Diabetes Mellitus Tipo 2/complicações , Jejum/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Obesidade Pediátrica/diagnóstico , Obesidade Pediátrica/metabolismo , Período Pós-Prandial/fisiologia , Índice de Gravidade de Doença , Estados Unidos
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