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We investigated the effects of oral administration of ß-cryptoxanthin (ß-CRX), a precursor of vitamin A synthesis, on the transcriptomes of peripheral neutrophils and liver tissue in post-weaned Holstein calves with immature immunity. A single oral administration of ß-CRX (0.2 mg/kg body weight) was performed in eight Holstein calves (4.0 ± 0.8 months of age; 117 ± 10 kg) on Day 0. Peripheral neutrophils (n = 4) and liver tissue (n = 4) were collected on Days 0 and 7. Neutrophils were isolated by density gradient centrifugation and treated with the TRIzol reagent. mRNA expression profiles were examined by microarray and differentially expressed genes were investigated using the Ingenuity Pathway Analysis software. The differentially expressed candidate genes identified in neutrophils (COL3A1, DCN, and CCL2) and liver tissue (ACTA1) were involved in enhanced bacterial killing and maintenance of cellular homoeostasis respectively. The changes in the expression of six of the eight common genes encoding enzymes (ADH5 and SQLE) and transcription regulators (RARRES1, COBLL1, RTKN, and HES1) were in the same direction in neutrophils and liver tissue. ADH5 and SQLE are involved in the maintenance of cellular homoeostasis by increasing the availability of substrates, and RARRES1, COBLL1, RTKN, and HES1 are associated with the suppression of apoptosis and carcinogenesis. An in silico analysis revealed that MYC, which is related to the regulation of cellular differentiation and apoptosis, was the most significant upstream regulator in neutrophils and liver tissue. Transcription regulators such as CDKN2A (cell growth suppressor) and SP1 (cell apoptosis enhancer) were significantly inhibited and activated, respectively, in neutrophils and liver tissue. These results suggest that oral administration of ß-CRX promotes the expression of candidate genes related to bactericidal ability and regulation of cellular processes in peripheral neutrophils and liver cells in response to the immune-enhancing function of ß-CRX in post-weaned Holstein calves.
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Neutrófilos , Transcriptoma , Animales , Bovinos , beta-Criptoxantina/metabolismo , Hígado/metabolismo , Análisis por Micromatrices/veterinariaRESUMEN
We investigated changes in rumen fermentation, peripheral blood metabolites and hormones, and hepatic transcriptomic dynamics in Holstein cows with and those without subacute ruminal acidosis (SARA) during the periparturient period. Sixteen multiparous Holstein cows were categorized in the SARA (n = 8) or non-SARA (n = 8) groups depending on whether they developed SARA during the 2 wk after parturition. Reticulo-ruminal pH was measured continuously throughout the study. Rumen fluid, blood, and liver tissue samples were collected at 3 wk prepartum and 2 and 6 wk postpartum, with an additional blood sample collected at 0 and 4 wk postpartum. The 1-h mean pH was depressed postpartum in both groups, whereas depression was more severe in the SARA group simultaneously with significantly longer duration of time (for pH <5.6 and 5.8). Significant expression of differentially expressed genes in liver tissue (DEGs; false discovery rate corrected P < 0.1) were identified only in the non-SARA group and were further analyzed by Ingenuity Pathway Analysis software. Among the top expressed DEGs, the hepatic genes encoding lipid and cholesterol secretion (APOA1, APOA4, and G0S2) and gluconeogenesis (PC, G6PC, and PCK1) were upregulated postpartum. In silico analysis revealed the significant postpartum activation of upstream regulators, such as INSR, PPARG, and PPARGC1A. These results suggested that hepatic transcriptomic responsiveness to postpartum metabolic load and hormones were likely discouraged in cows with SARA when compared with the significant activation of genes and signaling pathways for adequate metabolic adaption to postpartum high-grain diet feeding in Holstein cows without SARA.
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Acidosis/veterinaria , Hígado/fisiología , Rumen/metabolismo , Gastropatías/veterinaria , Acidosis/metabolismo , Animales , Peso Corporal , Bovinos , Enfermedades de los Bovinos/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hormonas/sangre , Concentración de Iones de Hidrógeno , Parto , Periodo Posparto , Rumen/fisiopatología , Gastropatías/metabolismoRESUMEN
Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.
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Cilostazol/metabolismo , Inhibidores de Fosfodiesterasa 3/metabolismo , Adulto , Disponibilidad Biológica , Cilostazol/administración & dosificación , Femenino , Humanos , Masculino , Farmacocinética , Inhibidores de Fosfodiesterasa 3/administración & dosificación , República de CoreaRESUMEN
The authors have elected to retract this paper in accordance with the following points. The article as written contains misleading information and omits important details. Cows in this study were assigned to groups based on the current definition of subacute ruminal acidosis; they were housed on two different farms and fed two different sets of rations in this study. However, multiple farms were not described in the materials and methods and this was not accounted for in the statistical analysis as published. The diets shown in Table 1 were not actually fed to animals; rather, the proportions of ingredients listed represent an average of the two farms housing the cows. The authors regret the errors.
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Acidosis/veterinaria , Bacterias/aislamiento & purificación , Enfermedades de los Bovinos/microbiología , Ácidos Grasos Volátiles/análisis , Microbioma Gastrointestinal , Acidosis/metabolismo , Acidosis/microbiología , Animales , Bacterias/genética , Bovinos , Enfermedades de los Bovinos/metabolismo , Dieta/veterinaria , Femenino , Fermentación , Concentración de Iones de Hidrógeno , Parto , Embarazo , Prevotella/genética , Prevotella/aislamiento & purificación , Rumen/metabolismo , Rumen/microbiologíaRESUMEN
The transcription factor cAMP-responsive element-binding protein (CREB) is involved in a variety of physiologic processes. Although its activity appears to be largely correlated with its phosphorylation status, cAMP-mediated dephosphorylation and the subsequent nuclear migration of the CREB-regulated transcription factors (CRTCs) are required to stimulate CREB transcriptional activity. Among the 3 identified mammalian homologs of CRTCs, CRTC3 has been shown to be expressed predominantly in adipose tissues in response to catecholamine signals that regulate lipid metabolism. Here, we show that prolonged cAMP signaling down-regulates CRTC3 in a proteasome-dependent manner and that neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L), a specific ubiquitin ligase for CRTC3, is responsible for this process. By recognizing the PY motif of CRTC3, NEDD4L interacts with CRTC3 and promotes its polyubiquitination. Interaction between NEDD4L and CRTC3 is further boosted by cAMP signaling, and this enhanced interaction appears to be dependent on the cAMP-mediated phosphorylation of NEDD4L at the Ser448 site. Furthermore, we show that food withdrawal stimulates NEDD4L phosphorylation in mice, which then show a decrease of adipose tissue CRTC3 protein levels. Together, these results suggest that NEDD4L plays a key role in the feedback regulation of cAMP signaling by limiting CRTC3 protein levels.-Kim, Y.-H., Yoo, H., Hong, A.-R., Kwon, M., Kang, S.-W., Kim, K., Song, Y. NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3.
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AMP Cíclico/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Factores de Transcripción/metabolismo , Ubiquitinación , Células 3T3 , Tejido Adiposo/metabolismo , Animales , Sitios de Unión , Retroalimentación Fisiológica , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas Nedd4/genética , Unión Proteica , Transducción de Señal , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.
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Anticoagulantes/farmacología , Hirudinas/farmacología , Modelos Biológicos , Fragmentos de Péptidos/farmacología , Adulto , Anticoagulantes/farmacocinética , Simulación por Computador , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Montecarlo , Fragmentos de Péptidos/farmacocinética , Tiempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
We investigated the effects of active dried Saccharomyces cerevisiae (ADSC) on ruminal pH, fermentation, and the fluid bacterial community during the short-term ruminal acidosis challenge. Five rumen-fistulated male Holstein calves (147.0 ± 5.8 kg of body weight; 3.6 ± 0.2 mo of age) were used in a crossover design, and 0 g (control group, n = 5) or 2 g (SC group, n = 5) of ADSC (1 × 1010 cfu/g) was administered twice daily for 21 consecutive days. Calves were fed a high-forage diet during the first 15 d (d -14 to d 0; prechallenge), a high-grain diet for 2 d (d 1 and 2; ruminal acidosis challenge), and a high-forage diet for 4 d (d 3 to 6; postchallenge). Ruminal pH was measured continuously. Rumen fluid samples were collected once daily (0800 h) on d 0, 3, 4, and 6 and twice daily (0800 and 1100 h) on d 1 and 2. Bacterial DNA was extracted from fluid samples collected on d 0 and 3. The 24-h and 1-h mean ruminal pH was significantly depressed during the ruminal acidosis challenge in each group, although the changes were more severe in the SC group, consistent with a significant increase in lactic acid on d 2 (1100 h) compared with d 0 and a significantly higher proportion of butyric acid on d 2 (1100 h) compared with the control group. Feeding a high-grain diet caused a decrease in bacterial diversity due to high acidity in both groups. The relative abundances of the genus Bifidobacterium and operational taxonomic unit (OTU) 3 (Bifidobacterium species) increased significantly in both groups but were higher in the SC group. Correlation analyses indicated that OTU3 (Bifidobacterium species) were positively correlated with lactic acid concentration and that OTU1 (Prevotella species) and OTU5 (Succinivibrio species) were correlated with the proportion of butyric acid. These results suggest that ADSC supplementation induced the intense decreases in ruminal pH by increased butyric and lactic acid production through a high-grain diet fermentation by rumen fluid bacterial species during the short-term ruminal acidosis challenge in Holstein calves after weaning.
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Acidosis/veterinaria , Enfermedades de los Bovinos/microbiología , Rumen/microbiología , Saccharomyces cerevisiae/metabolismo , Acidosis/metabolismo , Acidosis/microbiología , Alimentación Animal , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Butiratos/metabolismo , Bovinos , Enfermedades de los Bovinos/metabolismo , Dieta/veterinaria , Suplementos Dietéticos/análisis , Grano Comestible , Fermentación , Concentración de Iones de Hidrógeno , Masculino , Rumen/química , Rumen/metabolismo , Levadura SecaRESUMEN
Although melanin production is a key self-defense mechanism against ultraviolet radiation (UVR)-induced skin damage, uneven or excessive deposition of melanin causes hyperpigmentary disorders. Currently available whitening agents are unsatisfactory because of issues with efficacy and safety. To develop more effective depigmenting agents, we performed high-throughput melanin content assay screening using the B16F10 melanoma cell line and identified L-765,314 as a drug that suppressed melanin production in cultured melanocytes in a dose-dependent manner as well as cAMP- or 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated melanin production without cytotoxicity. Interestingly, melanogenic gene expression was not altered by L-765,314. Rather, diminished melanin production by L-765,314 appeared to be caused by downregulation of tyrosinase activity via inhibition of protein kinase C (PKC). Because L-765,314 did not show any adverse effect in melanocytes, altogether our data suggest that L-765,314 could be a potential therapeutic candidate for skin hyperpigmentary disorders and further discovery of selective inhibitors targeting PKC might be a promising strategy for the development of depigmenting agents to treat hyperpigmentary disorders.
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Blanqueadores/farmacología , Inhibidores Enzimáticos/farmacología , Melaninas/antagonistas & inhibidores , Monofenol Monooxigenasa/antagonistas & inhibidores , Prazosina/análogos & derivados , Proteína Quinasa C/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Blanqueadores/química , AMP Cíclico/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Regulación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Melaninas/biosíntesis , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , Prazosina/química , Prazosina/farmacología , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/química , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND AND OBJECTIVE: Massive retroperitoneal hematoma caused by lumbar artery rupture is generally associated with trauma or retroperitoneal malignancy. However, despite recent advances in technologies and tools, spontaneous lumbar artery rupture is a very rare disease entity but remains a challenging problem because it is frequently associated with significantly high mortality and morbidity and is very difficult to make a correct diagnosis. METHODS: We evaluated the databases of the PubMed, Embase, Cochrane Central Register of Controlled Trial, Google Scholar, the KoreaMed and the Research Information Sharing Service databases, and a detailed systematic review was performed by searching in PubMed. The initial search was performed on 3 February 2018 and a second search conducted in 29 January 2019. RESULTS: A total of 10 case reports on massive hemoperitoneum caused by spontaneous lumbar artery rupture were identified. Of the 10 case reports involving 14 patients, eight were male and six were female under 62.71 ± 13.93. Of the 14 patients, 9 (64.3%) surviving with transcatheter arterial embolization, three (21.4%) died of multi-organ failure or hypovolemia, and two (14.3%) had no definite records on survival or death. CONCLUSIONS: A massive retroperitoneal hematoma caused by lumbar artery rupture should be considered in patients with late-onset shock accompanied by blunt abdominal/pelvic trauma. Furthermore, early detection and urgent embolization would prevent further complications and eliminate the need for surgical interventions.
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BACKGROUND: Subacute ruminal acidosis (SARA) is characterized by a ruminal pH depression, and microbiota can also be affected by a higher acidity and/or dietary changes. Previous studies have revealed similar patterns in pH reduction in the rumen and reticulum, whereas changes in reticular pH and bacterial community following a high-grain diet are not fully understood. The aim of this study was to investigate the changes in reticular pH and bacterial community structure following a high-grain diet simultaneously with those in the rumen. RESULTS: SARA was diagnosed when ruminal and reticular pH remained under 5.6 for 350 ± 14 and 312 ± 24 min/d, respectively, on the last day of the CON period. During the CON period, lower proportion of acetic acid and higher proportion of butyric acid were observed compared with the HAY period. The proportions of acetic acid and propionic acid were lower and higher, respectively, in the rumen compared with the reticulum. From 454 pyrosequencing analysis, the relative abundance of several genera differed significantly between the two periods and the two locations. During the HAY period, higher relative abundances of Prevotella, Eubacterium, Oscillibacter, and Succiniclasticum and lower relative abundances of Ruminococcus, Clostridium, and Olsenella were identified compared with the CON period. Furthermore, the relative abundance of Eubacterium was lower in the rumen compared with the reticulum. Bacterial diversity indices were significantly different between the HAY and CON periods, being higher in the HAY period. The quantitative real-time PCR showed that the copy numbers of several cellulolytic bacteria (Fibrobacter succinogenes and Ruminococcus albus) were higher during the HAY period. CONCLUSION: A high-grain diet showed similar impacts on the pH, fermentation, and bacterial community structure in the rumen and reticulum. During the CON period, ruminal and reticular pH decreased following the high-grain challenge, and lower bacterial diversity and changes in the bacterial composition, similarity, and bacterial copy numbers were observed due to a higher acidity and dietary changes compared with the HAY period. These changes may influence the fermentative ability of the rumen and reticulum.
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Acidosis/veterinaria , Enfermedades de los Bovinos/microbiología , Reticulum/metabolismo , Rumen/metabolismo , Acidosis/microbiología , Alimentación Animal/análisis , Animales , Bacterias/clasificación , Bacterias/genética , Bovinos , Dieta/veterinaria , Grano Comestible/efectos adversos , Fermentación , Microbioma Gastrointestinal , Concentración de Iones de Hidrógeno , Reticulum/microbiología , Rumen/microbiologíaRESUMEN
We investigated the effect of repeated subacute ruminal acidosis (SARA) challenges on the pH, fermentative function, and bacterial community in the rumen. Four rumen-cannulated Holstein bulls were fed a high-forage diet for 7 d (HF period) followed by a high-grain diet for 7 d (HG period). Four SARA challenges were carried out consecutively (first, second, third, and fourth challenges). The ruminal pH was measured continuously during the experiment, and rumen fluid samples during the first to fourth challenges were collected at 0800, 1400, and 2000 h on the last days of each feeding period for analysis; volatile fatty acid components, NH3-N, and lactic acid concentrations were measured. Bacterial community structure was analyzed at 0800 h during the first and fourth challenges on the last days of each period. The 24-h mean ruminal pH was decreased during the transition from high-forage to high-grain diet and tended to differ between the HF and HG periods. During the HG period, ruminal pH <5.6 was maintained for a longer period in the first and second challenges (350 and 405 min/d, respectively) than in the third and fourth challenges (both 120 min/d). A marked increase in total volatile fatty acid and NH3-N concentrations during the HG period was observed in the later challenges. In addition, lower and higher proportions of acetic and butyric acids, respectively, were observed during the HG period than during the HF period. A total of 37 core bacterial genera were found in all samples; however, the relative abundance of several genera differed significantly between the HF and HG periods (Prevotella, Ruminococcus, Eubacterium, and Oscillibacter) and between the first and fourth challenges (Eubacterium and unclassified Clostridiaceae). During the HG period, lower relative abundances of Prevotella, Eubacterium, and Oscillibacter and higher relative abundance of Ruminococcus were detected compared with during the HF period. The relative abundances of Eubacterium and unclassified Clostridiaceae were lower in the first challenge than in the fourth challenge. Bacterial diversity was greater during the HF period than during the HG period and was greater during the fourth challenge than during the first challenge. Interestingly, diversity indices during the HG period of the fourth challenge were higher than those during the HF period of the first challenge. These results suggested that rumen fermentation in Holstein cattle can adapt to repeated SARA challenges by minimizing the adverse changes in ruminal pH. Moreover, the composition and diversity of the ruminal bacterial community may be affected by ruminal pH and vice versa.
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Acidosis/veterinaria , Bacterias/aislamiento & purificación , Enfermedades de los Bovinos/microbiología , Microbioma Gastrointestinal , Rumen/microbiología , Acidosis/metabolismo , Acidosis/microbiología , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/metabolismo , Biodiversidad , Butiratos/metabolismo , Bovinos , Enfermedades de los Bovinos/metabolismo , Grano Comestible/química , Grano Comestible/metabolismo , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Femenino , Fermentación , Concentración de Iones de Hidrógeno , Masculino , Rumen/química , Rumen/metabolismoRESUMEN
We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holstein calves were assigned to groups fed calf starter either with forage (HAY group, n = 3) or without forage (CON group, n = 4). Ruminal pH was measured continuously, and rumen fluid and epithelium were collected 3 wk after weaning. mRNA expression profiles of the RE were examined by one-color microarray. Differentially expressed genes (DEGs) were investigated using the Ingenuity Pathway Analysis (IPA). Mean and maximum ruminal pH were significantly (P < 0.05) higher, and the duration of pH < 5.8 during 1 day was significantly (P < 0.05) shorter, in the HAY group. The proportion of ruminal acetate and the acetate-to-propionate ratio were significantly (P < 0.05) lower in the CON group. DEGs encoding transcription regulators (SREBP1), insulin-like growth factor binding proteins (IGFBP7 and CTGF), ketogenic enzymes (HMGCL, BDH1, and BDH2), and a transporter (SLC16A3) were identified (P < 0.05) between the two groups. A growth factor (TGFB1) and signaling pathway (EGF and EGFR) were activated as upstream regulators. These results suggest that dietary forage alleviates ruminal acidosis, and the decrease in ruminal pH may damage the RE, leading to changes in gene expression to repair the damage. Furthermore, rumen development may be regulated by growth factor (TGFB1) and signaling pathways (EGF and IGFBP) for adaptation to feeding on calf starter with and without forage during the weaning transition.
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Adaptación Fisiológica/genética , Alimentación Animal , Dieta , Epitelio/metabolismo , Rumen/metabolismo , Transcriptoma/genética , Destete , Animales , Bovinos , Colesterol/biosíntesis , Ácidos Grasos Volátiles/metabolismo , Regulación de la Expresión Génica , Concentración de Iones de Hidrógeno , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. METHODS: This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. RESULTS: Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. CONCLUSION: A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.
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Inhibidores de la Colinesterasa/farmacocinética , Indanos/farmacocinética , Modelos Biológicos , Piperidinas/farmacocinética , Adulto , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/sangre , Donepezilo , Voluntarios Sanos , Humanos , Indanos/administración & dosificación , Indanos/sangre , Masculino , Piperidinas/administración & dosificación , Piperidinas/sangre , Parche Transdérmico , Adulto JovenRESUMEN
OBJECTIVES: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.
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Interacciones Alimento-Droga , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Esquema de Medicación , Combinación de Medicamentos , Ayuno/sangre , Semivida , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/sangre , Masculino , Tasa de Depuración Metabólica , Metformina/administración & dosificación , Metformina/efectos adversos , Metformina/sangre , Piperidonas/administración & dosificación , Piperidonas/efectos adversos , Piperidonas/sangre , Periodo Posprandial , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/sangre , República de Corea , Factores Sexuales , Comprimidos , Adulto JovenRESUMEN
This study aimed to investigate effects of long-term probiotic supplementation on gut microbiota and growth performance in health weaned piglets. The non-probiotic group (N-PrB) was fed only a basal diet, while the probiotic group (PrB) was fed a basal diet + probiotic combination (E. faecium 1.6 × 108 CFU/g, B. subtilis 2.0 × 108 CFU/g, S. cerevisiae 3.0 × 108 CFU/g). The probiotics combination was provided to the PrB, mixing with the basal diet in 5 kg/ton. As a result, the PrB exhibited significantly improved weight gain compared to the N-PrB (p = 0.00991). In the gut microbiome analysis, the PrB exhibited a significant increasing tendency of α-diversity compared to those of the N-PrB (p < 0.01). In the bacterial relative abundance changes in bacteria comprising the gut microbiota, Ruminococcaceae (p = 0.00281) and Prevotella (p = 0.00687) tended to significantly increase in the PrB, but decreased in the N-PrB. The Eubaterium coprostanoligenes group exhibited an increasing tendency in both groups, but tended to increase more significantly in the PrB compared to the N-PrB (p = 0.00681). Muribaculaceae tended to significantly increase in the N-PrB, but decreased in the PrB (p = 0.002779). In this study, significant differences on the gut microbiome were found according to the probiotics supplementation in the weaned piglets and these gut microbiome changes appeared to improve the growth performance.
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Objectives: To update recent information on contamination levels of mycotoxins in South Korea. Materials and methods: A total of 208 samples sourced from the feeds of swine farms were collected. The contamination levels of mycotoxins, which are aflatoxin (Afla), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEN), fumonisin (FUM), and T-2 toxin, were investigated by enzyme-linked immunosorbent assays (ELISAs). Results: The detection levels of the total samples were 78.91% for DON, 75.24% for Afla, 47.02% for ZEN, 68.31% for FUM, and 5.94% for OTA and T-2, which were not detected at all. Most of the analyzed mycotoxins showed significant high occurrences in 47.02%-78.91% of the swine feed samples. 11 of the 152 alfa-positive samples exceeded the maximum residue limit (MRL) of Afla proposed by the Korean regulation. In the analysis of mycotoxin detection levels by growth stage, ZEN was found in the nursery stage at a remarkably high concentration level (126.46 ± 63.76 ppb), exceeding the MRL of ZEN for piglets proposed by the European Commission. This mycotoxin was also found in the samples from the gestation barn (89.04 ± 46.05 ppb) and the farrowing house (105.58 ± 94.12) at a high concentration level. Afla was found in the nursery stage at a high concentration (8.00 ± 2.22 ppb), approaching the MRL (10 ppb) of Afla proposed by the Korean regulation. Conclusion: These results indicate that many swine farms in South Korea are still exposed to mycotoxin risk, and special attention and surveillance are necessary for these mycotoxin risks in swine farms.
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Objective: The aim of this investigation was to examine the impact of Taraxacum coreanum (known as dandelion) (TC) and TC mixtures with milk thistle (MT) or Aspergillus oryzae (AO) as feed additives on the immune response, milk quality, and milk production in Holstein cows over 6 weeks of administration. Materials and Methods: Thirty-two healthy Holstein dairy cows were provided 30 kg of total mixed ration (TMR) with no TC, 90 gm TC, 54 gm TC + 36 gm MT, or 54 gm TC + 36 gm AO 40% groups. The feed additives were supplied daily in two equal portions (per 45 gm) by topdressing the TMR for 6 weeks. Milk and blood samples were collected weekly. Results: In the TC-treated cows (TC, TC + MT, and TC + AO groups), significantly lower peripheral blood white blood cell (WBC) counts at 6 weeks and milk somatic cell counts (SCCs) at 4-6 weeks of administration were observed. Concentrations of serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) were notably elevated in cows treated with TC for 4-6 weeks, while levels of proinflammatory cytokines concentrations of tumor necrosis factor-alpha (TNF-α) and chemokine (IL-8) were significantly reduced in TC-treated cows after 3-6 weeks of administration. Conclusion: These results suggested that TC or a TC mixture with other medicinal herbs supplementations enhanced the serum antioxidative activities and, consequently, might suppress the adverse immune response due to lower serum TNF-α and IL-8 release supported by lower WBC and SCC counts.
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BACKGROUND: Implant-based breast reconstruction has evolved over time. However, the effects of prepectoral breast reconstruction (PBR) compared with those of subpectoral breast reconstruction (SBR) have not been clearly defined. Therefore, this study aimed to compare the occurrence of surgical complications between PBR and SBR to determine the procedure that is effective and relatively safe. METHODS: The PubMed, Cochrane Library, and EMBASE databases were searched for studies published until April of 2021 comparing PBR and SBR following mastectomy. Two authors independently assessed the risk of bias. General information on the studies and surgical outcomes were extracted. Among 857 studies, 34 and 29 were included in the systematic review and meta-analysis, respectively. Subgroup analysis was performed to clearly compare the results of patients who underwent postmastectomy radiation therapy. RESULTS: Pooled results showed that prevention of capsular contracture (OR, 0.57; 95% CI, 0.41 to 0.79) and infection control (OR, 0.73; 95% CI, 0.58 to 0.92) were better with PBR than with SBR. Rates of hematoma, implant loss, seroma, skin-flap necrosis, and wound dehiscence were not significantly different between PBR and SBR. PBR considerably improved postoperative pain, BREAST-Q score, and upper arm function compared with SBR. Among postmastectomy radiation therapy patients, the incidence rates of capsular contracture were significantly lower in the PBR group than in the SBR group (OR, 0.14; 95% CI, 0.05 to 0.35). CONCLUSIONS: The results showed that PBR had fewer postoperative complications than SBR. The authors' meta-analysis suggests that PBR could be used as an alternative technique for breast reconstruction in appropriate patients.
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Implantación de Mama , Implantes de Mama , Neoplasias de la Mama , Contractura , Mamoplastia , Humanos , Femenino , Neoplasias de la Mama/etiología , Mastectomía/efectos adversos , Mastectomía/métodos , Implantación de Mama/efectos adversos , Implantación de Mama/métodos , Mamoplastia/efectos adversos , Mamoplastia/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Contractura/etiología , Implantes de Mama/efectos adversosRESUMEN
Recently, polymer-based tissue adhesives (TAs) have gained the attention of scientists and industries as alternatives to sutures for sealing and closing wounds or incisions because of their ease of use, low cost, minimal tissue damage, and short application time. However, poor mechanical properties and weak adhesion strength limit the application of TAs, although numerous studies have attempted to develop new TAs with enhanced performance. Therefore, next-generation TAs with improved multifunctional properties are required. In this review, we address the requirements of polymeric TAs, adhesive characteristics, adhesion strength assessment methods, adhesion mechanisms, applications, advantages and disadvantages, and commercial products of polysaccharide (PS)-based TAs, including chitosan (CS), alginate (AL), dextran (DE), and hyaluronic acid (HA). Additionally, future perspectives are discussed.