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AIMS: MND-2119 is a novel once-daily dose self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) and is approved as an antihyperlipidemia agent in Japan. It has improved absorption and achieves higher plasma EPA concentrations at Cmax than conventional EPA-E. In the JELIS trial, concomitant use of EPA-E with statin therapy significantly reduced atherosclerotic cardiovascular disease (ASCVD) risks. As a potential mechanism of action of EPA, endogenous formation of EPA-derived anti-inflammatory metabolites is receiving greater attention. This study aims to investigate the endogenous formation of EPA-derived anti-inflammatory metabolites following single and multiple administrations of MND-2119. METHODS: Healthy adult male subjects were randomly assigned to a nonintervention (control) group, MND-2119 2-g/day group, MND-2119 4-g/day group, or EPA-E 1.8-g/day group for 7 days (N=8 per group). Plasma fatty acids and EPA-derived metabolites were evaluated. Peripheral blood neutrophils were isolated, and the production of EPA-derived metabolites from in vitro stimulated neutrophils was evaluated. RESULTS: After single and multiple administrations of MND-2119 2 g/day, there were significant increases in plasma EPA concentration, 18-hydroxyeicosapentaenoic acid (18-HEPE), and 17,18-epoxyeicosatetraenoic acid compared with those of EPA-E 1.8 g/day. They were further increased with MND-2119 4 g/day administration. In neutrophils, the EPA concentration in the MND-2119 2-g/day group was significantly higher compared with that in the EPA-E 1.8-g/day group after multiple administration, and 18-HEPE production was positively correlated with EPA concentration. No safety issues were noted. CONCLUSIONS: These results demonstrate that MND-2119 increases the plasma and cellular concentrations of EPA and EPA-derived metabolites to a greater extent than conventional EPA-E formulations.
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Ácidos Docosahexaenoicos , Ésteres , Adulto , Humanos , Masculino , Ácido Eicosapentaenoico , Ácidos Grasos , Antiinflamatorios , Administración OralRESUMEN
PURPOSE: To investigate the effects of lactoferrin (LF) on infectious diseases in Japanese summer. METHODS: An intake of placebo, 200 mg, or 600 mg of LF were administered to healthy adults in Kyushu University of Health and Welfare for 12 weeks in a randomized, double-blinded, placebo-controlled parallel-group comparative trial. The primary endpoints were the prevalence and duration of infectious diseases and changes in immune parameters. RESULTS: Three hundred and ten subjects were randomized (placebo, n = 104; 200 mg, n = 103; 600 mg, n = 103). Twenty subjects were lost to the follow-up, leaving 290 for a full analysis set (n = 99; n = 95; n = 96). The duration (day) of total infectious diseases was shorter in the 200 mg group (2.0, p = 0.045) and 600 mg group (2.0, p = 0.010) than in the placebo group (3.0). The duration of summer colds was shorter in the 600 mg group (2.0, p = 0.036) than in the placebo group (3.0). No significant differences were observed in the prevalence of infectious diseases or changes in immune parameters. In exploratory investigations, changes in the neutrophil phagocytic capacity, cortisol concentrations, and T score of "Vigor/Activity" in the Profile of Mood States 2 were greater in the 600 mg group than in the placebo group, when analysis was done on the lower half groups at the baseline. Adverse events were similar in each group and none had a causal relationship with the intake of the test foods. CONCLUSIONS: In summer, the intake of LF attenuates infectious diseases, including summer colds.
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Antiinfecciosos/uso terapéutico , Resfriado Común/tratamiento farmacológico , Enfermedades Transmisibles/tratamiento farmacológico , Lactoferrina/uso terapéutico , Estaciones del Año , Adulto , Anciano , Resfriado Común/epidemiología , Enfermedades Transmisibles/epidemiología , Método Doble Ciego , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Human noroviruses cause significant morbidity and mortality worldwide, but lack approved antivirals or vaccines to treat or prevent infections. The recent development of two cell culture systems in human transformed B cells (BJABs) and non-transformed human intestinal enteroid cultures overcomes a main limitation in identifying molecules with anti-norovirus activities. Lactoferrin is an iron-binding glycoprotein found in the milk of most mammals, with broad spectrum antimicrobial activities, including against the related murine norovirus in cell culture. In a Japanese clinical trial, ingestion of lactoferrin reduced the incidence of infectious gastroenteritis in the participants. Because human noroviruses were the most common cause of gastroenteritis in Japan during the clinical trial period, we sought to determine whether lactoferrin could inhibit infection with human norovirus. Our study, using a B cell culture model, demonstrates that lactoferrin reduces human norovirus infection. The mechanism of antiviral action is likely indirect and may involve the induction of innate interferon responses. Therefore, future studies are warranted to test the antiviral efficacy of lactoferrin against human norovirus infection in patients.
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Antivirales/farmacología , Lactoferrina/metabolismo , Norovirus/efectos de los fármacos , Animales , Antivirales/química , Bovinos , Células Cultivadas , Humanos , Lactoferrina/química , Pruebas de Sensibilidad Microbiana , Replicación Viral/efectos de los fármacosRESUMEN
Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.
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Huesos/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Linagliptina/farmacología , Administración Oral , Animales , Densidad Ósea/efectos de los fármacos , Huesos/anomalías , Huesos/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Polipéptido Inhibidor Gástrico/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Linagliptina/administración & dosificación , Linagliptina/uso terapéutico , Masculino , Ratones , Ratones Obesos , Osteocalcina/sangre , Osteocalcina/efectos de los fármacos , Fosfatasa Ácida Tartratorresistente/sangre , Fosfatasa Ácida Tartratorresistente/efectos de los fármacosRESUMEN
Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.
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Enfermedades Óseas Metabólicas/tratamiento farmacológico , Inmunosupresores/efectos adversos , Ácido Risedrónico/uso terapéutico , Tacrolimus/efectos adversos , Vitamina K 2/análogos & derivados , Animales , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/inducido químicamente , Quimioterapia Combinada , Fémur/efectos de los fármacos , Fémur/fisiología , Masculino , Osteogénesis/efectos de los fármacos , Ratas Wistar , Tibia/efectos de los fármacos , Tibia/fisiología , Vitamina K 2/uso terapéuticoRESUMEN
Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-ß protein precursor transgenic (AßPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AßPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aß40 and Aß42 levels through the inhibition of amyloidogenic processing of AßPP, as it decreased ß-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aß in primary astrocyte cultures. These findings indicate that the reduction in Aß levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aß in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.
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Péptidos beta-Amiloides/biosíntesis , Suplementos Dietéticos , Lactoferrina/uso terapéutico , Trastornos de la Memoria/prevención & control , Transportador 1 de Casete de Unión a ATP/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteínas E/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Astrocitos/metabolismo , Química Encefálica/efectos de los fármacos , Dieta , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Cultivo Primario de Células , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To evaluate the effect of tablets containing lactoferrin (LF) and lactoperoxidase (LPO) on gingival health and oral health-related quality of life in healthy adults. BACKGROUND: Lactoferrin and LPO are host defense factors found in saliva that may contribute to oral health. MATERIALS AND METHODS: One hundred and fifty adults were randomly assigned to the administration of high-dose tablets (LF 60 mg/d, LPO 7.8 mg/d), low-dose tablets (LF 20 mg/d, LPO 2.6 mg/d), or placebo tablets for 12 weeks. The gingival index (GI) and plaque index (PlI) were measured at baseline and after 12 weeks. Oral health-related quality of life was assessed by the Oral Health Impact Profile (OHIP) at baseline and at 4, 8, and 12 weeks. RESULTS: One hundred and nine healthy subjects were included in the efficacy analysis. In the high-dose group, the GI was significantly reduced after 12 weeks of treatment, and the reduction in GI in the high-dose group was significant compared with the placebo group. In both the high-dose group and the low-dose group, PlI showed a significant decrease at 12 weeks compared with baseline. The total OHIP score was significantly reduced at 12 weeks in the high-dose group. In addition, the OHIP functional limitation subscale displayed significant improvement in the high-dose groups compared with the placebo group at 12 weeks. No adverse reactions or serious adverse events related to the test tablets were observed in any of participants during the study, and the incidence of adverse events unrelated to the tablets did not differ significantly among the groups. CONCLUSION: These results suggest that intake of tablets containing LF (60 mg/d) and LPO (7.8 mg/d) can potentially improve gingival inflammation and oral health-related quality of life in healthy adults.
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Inflamación/prevención & control , Lactoferrina/uso terapéutico , Lactoperoxidasa/uso terapéutico , Salud Bucal , Adulto , Índice de Placa Dental , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice Periodontal , Calidad de Vida , ComprimidosRESUMEN
Candida albicans is a commensal fungus in human mucosal surfaces, including the oral cavity. Lactoferrin (LF) and the lactoperoxidase (LPO) system, which are host protection components in exocrine secretions, each exhibit weak anti-candida activity. We herein examined the effects of the combination of LF and the LPO system on C. albicans. Morphological observations indicated that the combination of LF and the LPO system reduced the mycelial volume of C. albicans and changed the size and shape of cells more than each agent alone. The combination of LF and the LPO system also exerted strong inhibitory effects on the cellular metabolic activity and adhesive hyphal form of C. albicans. A checkerboard analysis revealed that the anti-candida activity of LF and the LPO system was synergistic. These results suggest that the combination of LF and the LPO system is useful for preventing candidiasis.
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Antifúngicos/administración & dosificación , Candida albicans/efectos de los fármacos , Lactoferrina/administración & dosificación , Lactoperoxidasa/administración & dosificación , Animales , Antifúngicos/metabolismo , Candida albicans/crecimiento & desarrollo , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Bovinos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Lactoferrina/metabolismo , Lactoperoxidasa/metabolismoRESUMEN
OBJECTIVES: Lactoferrin (LF) and lactoperoxidase (LPO) are present in human saliva. LF has been demonstrated to show antibacterial and antiviral activities. In saliva, LPO catalyzes the hydrogen peroxide-dependent oxidation of thiocyanate to hypothiocyanite that exhibits antimicrobial and antiviral properties. A randomized, open-label, parallel-group clinical trial was conducted to examine the effectiveness of sucking tablets containing LF and LPO (LF+LPO) in alleviating symptoms of the common cold and/or influenza infection. METHODS: A total of 407 subjects were randomized into two groups, treatment and non-treatment groups, and each group was further classified into subgroups habitually wearing a face mask, washing their hands, or gargling. The common cold, influenza, and gastrointestinal symptoms were used to evaluate the effectiveness, and the incidence and duration of symptoms were statistically analyzed. RESULTS: The incidence and duration of common cold, gastrointestinal symptoms, and influenza infection were not statistically different between treatment and non-treatment groups. LF+LPO tablets were moderately effective in reducing the incidence and duration of common cold symptoms in the subgroup that did not gargle and especially to shorten significantly the duration of fever higher than 38°C in the subgroup that did not wear a face mask. CONCLUSION: The results suggested that the effect of ingestion of the tablet is not obvious in alleviating common cold symptoms but may be helpful when the subjects do not follow precautionary measures such as gargling and the use of a protective face mask.
RESUMEN
AIM: It is known that the neutrophil-to-lymphocyte ratio(NLR)is associated with outcomes in patients with cancer. In this study, changes in the NLR and soluble programmed death-1 ligand-1(sPD-L1)levels were assessed in patients with metastatic colorectal cancer treated with chemotherapy. METHODOLOGY: Ten patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to April 2017 at the Niitsu Medical Center Hospital. The NLR was calculated based on complete blood counts obtained prior to the administration of chemotherapy. Serum sPD-L1 levels were measured by enzyme-linked immunosorbent assay. NLR and sPD-L1 level changes from baseline were compared with tumor response and tumor markers. RESULTS: A relationship was found between sPD-L1 levels and NLR after the treatment of metastatic colorectal cancer(r=0.241, p=0.0459). Decreased sPD-L1 levels were associated with reduced NLR and tumor marker levels. Increased sPD-L1 levels were not related to elevated tumor marker levels. CONCLUSION: Changes in the NLR and sPD-L1 levels during chemotherapy may have a uniquely predictive value in patients with CRC treated with chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/análisis , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Recuento de Leucocitos , Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , SolubilidadRESUMEN
Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.
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Densidad Ósea/efectos de los fármacos , Resorción Ósea , Calcificación Fisiológica/efectos de los fármacos , Inhibidores de la Calcineurina , Ciclosporina , Fémur/metabolismo , Osteogénesis/efectos de los fármacos , Tacrolimus , Animales , Resorción Ósea/inducido químicamente , Resorción Ósea/metabolismo , Resorción Ósea/patología , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/farmacología , Ciclosporina/efectos adversos , Ciclosporina/farmacología , Fémur/patología , Masculino , Osteoblastos/metabolismo , Osteoblastos/patología , Ratas , Ratas Wistar , Tacrolimus/efectos adversos , Tacrolimus/farmacologíaRESUMEN
Herein we review commercial bovine lactoferrin quality issues by describing an example of industrial production, the current status of global quality standardization, and quality-activity concerns for further discussion. Morinaga Milk Industry has been industrially producing bovine lactoferrin in Milei GmbH, Germany, since 1989. We delineate its production and quality as an example of safe and high-quality manufacturing. Currently, global standardization in the quality of bovine lactoferrin is progressing through Novel Food and GRAS in the EU and USA, respectively. Novel Food was applied or notified to seven lactoferrin manufacturers and GRAS was notified to three manufacturers, two of which are for infant use and one is for adult use, by the end of 2017. The specifications of these regulations are relatively high, including more than 95% lactoferrin purity in protein, which means that such companies can supply relatively high-grade lactoferrin. There appear to be several concerns regarding lactoferrin quality affecting activities, including contamination of lipopolysaccharide (LPS) and angiogenin, purity, and degradation of lactoferrin sample. Although LPS is immunologically toxic when invading the body, it is distributed normally in foods and the gut. However, an industrial lactoferrin sample may contain LPS at a maximum LPS/lactoferrin molecule ratio = 1/1724, which means 99.9% of the lactoferrin molecule is LPS-free. It is difficult to speculate that LPS contained in a lactoferrin sample affects its activities. Finally in order to achieve good and reproducible results, we make proposals to researchers a use of high-grade lactoferrin, careful storage, and indication the manufacturers' names and specifications in the paper.
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Lactoferrina/química , Lipopolisacáridos/química , Control de Calidad , Ribonucleasa Pancreática/química , Animales , Bovinos , Humanos , Lactoferrina/genéticaRESUMEN
Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a long-term administration of gabapentin should be regularly monitored for changes in bone mass.
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Anticonvulsivantes/efectos adversos , Densidad Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Resorción Ósea/inducido químicamente , Hueso Esponjoso/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Administración Oral , Aminas/efectos adversos , Animales , Resorción Ósea/diagnóstico por imagen , Hueso Esponjoso/fisiología , Ácidos Ciclohexanocarboxílicos/efectos adversos , Fémur/diagnóstico por imagen , Fémur/fisiología , Fracturas Óseas/inducido químicamente , Fracturas Óseas/prevención & control , Gabapentina , Humanos , Levetiracetam , Masculino , Osteoclastos/efectos de los fármacos , Fenitoína/efectos adversos , Piracetam/efectos adversos , Piracetam/análogos & derivados , Ratas , Ratas Sprague-Dawley , Tibia/diagnóstico por imagen , Tibia/fisiología , Tomografía Computarizada por Rayos X , Ácido gamma-Aminobutírico/efectos adversosRESUMEN
AIM: In order to determine if the changes in the neutrophil-to-lymphocyte ratio(NLR)can predict the timingof regimen alteration, the outcome of chemotherapy for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Thirty patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to December 2015 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to administration of chemotherapy and at the time of the best response. We defined the period with an NLR≤2.5 as the total interval of an NLR≤2.5. The role of the NLR in overall survival was determined by univariate and multivariate Cox regression models. RESULTS: The median overall survival was 27 months in patients with an NLR≤2.5(n=22)and 11 months in those with an NLR>2.5 (n=8)at the best response(p<0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The patients who survived for more than 3 years were introduced to a second-line treatment prior to achievingan NLR>2.5. The period with an NLR≤2.5(p=0.001)and prechemotherapy CA19-9(p<0.0001)were independent, significant predictors of better survival in multivariate analysis. CONCLUSION: The introduction of a new chemotherapeutic regimen prior to achievingan NLR>2.5 predicted better survival in patients with mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Linfocitos/citología , Neutrófilos/citología , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios RetrospectivosRESUMEN
Long-term treatment with antiepileptic drugs (AED) is associated with an elevated risk of bone fracture due to decreased bone mineral density (BMD). Phenytoin has been shown to affect bone metabolism adversely, whereas newly developed AEDs have not been studied. This study evaluated the effects of topiramate and lamotrigine on bone metabolism in rats. Five-week-old male Sprague-Dawley rats were treated orally with phenytoin (20 mg/kg), topiramate (5 or 20 mg/kg), or lamotrigine (2 or 10 mg/kg) daily for 12 weeks. Phenytoin reduced bone strength, measured by maximum load to failure of the femoral mid-diaphysis, along with reduced femur total BMD. Serum tartrate-resistant acid phosphatase-5b levels significantly increased after phenytoin treatment, while serum osteocalcin levels decreased after topiramate 20 mg/kg treatment. Furthermore, osteoblast surface and bone mineralizing surface were significantly lowered by topiramate. Lamotrigine treatment did not affect bone strength, BMD, or bone turnover. We demonstrated that phenytoin treatment significantly increased bone resorption and lowered BMD and bone strength. Since lamotrigine did not affect bone metabolism, it can be concluded that lamotrigine is safety medicine for bone health. Topiramate was associated with decreased bone formation, which may affect bone strength and BMD with chronic use. Thus, patients taking topiramate should be monitored for changes in BMD to avoid risk of fracture.
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Anticonvulsivantes/farmacología , Huesos/efectos de los fármacos , Huesos/metabolismo , Fructosa/análogos & derivados , Triazinas/farmacología , Animales , Biomarcadores , Densidad Ósea/efectos de los fármacos , Fructosa/farmacología , Inmunohistoquímica , Lamotrigina , Masculino , Ratas , Resistencia a la Tracción/efectos de los fármacos , TopiramatoRESUMEN
Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonists used as therapy for type 2 diabetes. However, clinical studies reported that the therapeutic modulation of PPARγ activity using TZDs may induce negative effects on bone metabolism. This study aimed to evaluate the effect of the TZD pioglitazone on bone metabolism in rats. Male Wistar rats were treated orally with pioglitazone 5 or 20 mg/kg daily for 24 weeks. Bone strength was evaluated using a 3-point bending method, and bone histomorphometry was analyzed. Bone mineral density (BMD) was measured using quantitative computed tomography, and serum biochemical markers were examined. Pioglitazone caused a decrease in cortical and trabecular BMD of whole femur. A reduction in bone strength properties of the femoral mid-diaphysis was observed in the 20 mg/kg pioglitazone treated group. Bone histomorphometric analysis revealed that osteoblast surface and mineralizing surface were decreased, whereas osteoclast surface and number were increased after treatment with 20 mg/kg pioglitazone. Altogether, this study demonstrated that pioglitazone may repress bone formation and facilitate bone resorption. The resulting imbalance of bone metabolism leads to a reduction in BMD with a subsequent increase in bone fragility.
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Huesos/metabolismo , Hipoglucemiantes/efectos adversos , Tiazolidinedionas/efectos adversos , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/inducido químicamente , Huesos/patología , Depresión Química , Relación Dosis-Respuesta a Droga , Fémur/metabolismo , Fémur/patología , Hipoglucemiantes/administración & dosificación , Masculino , Osteoblastos/metabolismo , Osteoblastos/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Osteogénesis/efectos de los fármacos , PPAR gamma/agonistas , Pioglitazona , Ratas Wistar , Tiazolidinedionas/administración & dosificaciónRESUMEN
The oral microbiota influences health and disease states. Some gram-negative anaerobic bacteria play important roles in tissue destruction associated with periodontal disease. Lactoferrin (LF) and lactoperoxidase (LPO) are antimicrobial proteins found in saliva; however, their influence on the whole oral microbiota currently remains unknown. In this randomized, double-blinded, placebo-controlled study, the effects of long-term ingestion of LF and LPO-containing tablets on the microbiota of supragingival plaque and tongue coating were assessed. Forty-six older individuals ingested placebo or test tablets after every meal for 8 weeks. The relative abundance of bacterial species was assessed by 16S rRNA gene high-throughput sequencing. Most of the bacterial species in supragingival plaque and tongue coating that exhibited significant decreases in the test group were gram-negative bacteria, including periodontal pathogens. Decreases in the total relative abundance of gram-negative organisms in supragingival plaque and tongue coating correlated with improvements in assessed variables related to oral health, such as oral malodor and plaque accumulation. Furthermore, there was significantly less microbiota diversity in supragingival plaque at 8 weeks in the test group than in the placebo group and low microbiota diversity correlated with improvements in assessed variables related to oral health. These results suggest that LF and LPO-containing tablets promote a shift from a highly diverse and gram-negative-dominated to a gram-positive-dominated community in the microbiota of supragingival plaque and tongue coating. This microbial shift may contribute to improvements in oral health, including oral malodor and state of the gingiva.
Asunto(s)
Bacterias/clasificación , Bacterias/efectos de los fármacos , Lactoferrina/farmacología , Lactoperoxidasa/farmacología , Microbiota/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Bacterias/genética , Biodiversidad , ADN Bacteriano , Placa Dental/microbiología , Método Doble Ciego , Femenino , Encía , Humanos , Masculino , Consorcios Microbianos/genética , Microbiota/genética , Salud Bucal , ARN Ribosómico 16S/genética , Saliva/química , Saliva/microbiología , Lengua/microbiologíaRESUMEN
AIM: The impact of neutrophil-to-lymphocyte ratio(NLR)changes on the outcome of chemotherapy for metastatic colorectalcancer (mCRC)was analyzed retrospectively. METHODOLOGY: Twenty seven patients with unresectable mCRC were administered chemotherapy from January 2005 to December 2014 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to the administration of chemotherapy and at the best response. We defined the period with NLR≤2.5 as the totalintervalof NLR≤2.5. The impact of NLR on overallsurvivalwas determined using univariate and multivariate Cox regression models. RESULTS: The median overall survival was 26 months in patients with an NLR≤5(n= 22), and 11 months in those with an NLR>5(n=5)before chemotherapy(p=0.03). The median overall survival was 31 months in patients with an NLR≤2.5(n=19), and 11 months in those with an NLR>2.5(n=8)at the best response(p< 0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The period with an NLR≤2.5 was the only independent, statistically significant predictor of better survival in multivariate analysis(p=0.001). CONCLUSION: The change of NLR may be a dynamic predictor of better survivalin patients with mCRC.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Linfocitos , Neutrófilos , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios RetrospectivosRESUMEN
We examined the in-vitro effects of bovine lactoferrin (LF) on the production of interferon-λ (IFN-λ), an antiviral cytokine important for the defense of enterocytes, using the human intestinal epithelial cell line HT-29. HT-29 cell cultures were treated with LF for 1 h, and the cultures were stimulated with polyinosinic-polycytidylic acid (poly I:C). LF increased the concentration of IFN-λ in the culture supernatant after stimulation in a dose-dependent manner. A similar increase in the concentration of IFN-λ was observed in the supernatant of cells washed between treatment with LF and stimulation with poly I:C. At 6 and 24 h after stimulation with poly I:C (early and late phases, respectively) treated cultures contained significantly higher concentrations of IFN-λ1 in the culture supernatant, and significantly higher IFN-λ1 and IFN-λ2 mRNA levels, than controls. These results suggest that LF activates the innate cellular immunity of the enterocytes to double-stranded RNA and increases the production of IFN-λ.
Asunto(s)
Antiinfecciosos/farmacología , Antivirales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/metabolismo , Lactoferrina/farmacología , Animales , Bovinos , Ensayo de Inmunoadsorción Enzimática , Células HT29 , Humanos , Interferón gamma/genética , Poli I-C/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
AIM: Lactoferrin and lactoperoxidase have antimicrobial effects against oral pathogens. This randomized, double-blinded, placebo-controlled parallel group study tested the efficacy of a lactoferrin and lactoperoxidase-containing tablet (LF + LPO tablet) in improving the oral hygiene status of older individuals. METHODS: A total of 46 participants (31 nursing home residents and 15 healthy older individuals) were randomly assigned to receive either lactoferrin and lactoperoxidase-containing tablets or placebo tablets, and were asked to suck on a tablet after every meal for 8 weeks. Oral and bacteriological assessments were carried out at baseline, 4 weeks and 8 weeks. RESULTS: A total of 47 participants (test group n = 20; mean age 80.4 ± 6.4 years; placebo group n = 17; mean age 85.9 ± 6.7 years) were included in the efficacy analysis. In the test group, the total number of bacteria in the tongue coating was significantly reduced at 4 and 8 weeks compared with that at baseline, and the number of Porphyromonas gingivalis and Fusobacterium nucleatum was significantly reduced at 8 weeks. The total number of bacteria and the number of P. gingivalis in the supragingival plaque were significantly reduced at 8 weeks. Furthermore, there was a significant difference in the change in the number of P. gingivalis in supragingival plaque at 8 weeks between the two groups. CONCLUSIONS: Lactoferrin and lactoperoxidase-containing tablet ingestion showed antibacterial effects on periodontal bacteria present in the tongue coating and supragingival plaque, indicating that long-term ingestion could improve the oral hygiene of older individuals. Geriatr Gerontol Int 2017; 17: 714-721.