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1.
Ann Hematol ; 99(5): 1049-1061, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32236735

RESUMO

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/análogos & derivados , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida
2.
PLoS One ; 15(1): e0226806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31905208

RESUMO

The emergence of creatine as a potential cognitive enhancement supplement for humans prompted an investigation as to whether supplemental creatine could enhance spatial memory in young swine. We assessed memory performance and brain concentrations of creatine and its precursor guanidinoacetic acid (GAA) in 14-16-week-old male Yucatan miniature pigs supplemented for 2 weeks with either 200 mg/kg∙d creatine (+Cr; n = 7) or equimolar GAA (157 mg/kg∙d) (+GAA; n = 8) compared to controls (n = 14). Spatial memory tests had pigs explore distinct sets of objects for 5 min. Objects were spatially controlled, and we assessed exploration times of previously viewed objects relative to novel objects in familiar or novel locations. There was no effect of either supplementation on memory performance, but pigs successfully identified novel objects after 10 (p < 0.01) and 20 min (p < 0.01) retention intervals. Moreover, pigs recognized spatial transfers after 65 min (p < 0.05). Regression analyses identified associations between the ability to identify novel objects in memory tests and concentrations of creatine and GAA in cerebellum, and GAA in prefrontal cortex (p < 0.05). The concentration of creatine in brain regions was not influenced by creatine supplementation, but GAA supplementation increased GAA concentration in cerebellum (p < 0.05), and the prefrontal cortex of +GAA pigs had more creatine/g and less GAA/g compared to +Cr pigs (p < 0.05). Creatine kinase activity and maximal reaction velocity were also higher with GAA supplementation in prefrontal cortex (p < 0.05). In conclusion, there appears to be a relationship between memory performance and guanidino compounds in the cerebellum and prefrontal cortex, but the effects were unrelated to dietary supplementation. The cerebellum is identified as a target site for GAA accretion.


Assuntos
Ração Animal/análise , Encéfalo/fisiologia , Creatina/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais , Glicina/análogos & derivados , Memória Espacial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Glicina/administração & dosagem , Masculino , Memória Espacial/efeitos dos fármacos , Suínos , Porco Miniatura , Desmame
3.
J Anim Sci ; 98(2)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31965147

RESUMO

A total of 96 newly weaned barrows (initial body weight [BW]: 6.3 ± 0.5 kg) were used to determine the effect of a low crude protein (CP) diet supplemented with Gly and Ser on growth and skin collagen abundance. Barrows were assigned to one of three experimental diets in a three-phase feeding program fed for 35 days (n = 8; pen was the experimental unit): 1) corn-soybean meal diet (CON; 20.3% to 23.1% CP; as-fed, analyzed contents); 2) low CP diet (14.8% to 21.4% CP) supplemented with Gly and Ser (G + S) to the same concentrations as CON; 3) low CP diet supplemented with Glu to maintain the same CP concentration as the G + S diet (GLU; 15.0% to 22.1% CP). On days 21 and 35, eight pigs per treatment were euthanized for the determination of physical and chemical body composition and skin collagen abundance. Pigs fed the CON diet had greater overall ADG and final BW compared to pigs fed GLU and G + S (P < 0.01). Over the entire 35-day experimental period, ADFI was not influenced by dietary treatment but G:F tended to be greater for pigs fed CON than G + S (P = 0.084), while intermediate values were observed for GLU. Carcass weights on days 21 and 35 were greater for pigs fed CON than G + S or GLU (P < 0.01). Viscera weights on day 21 were greater for CON than G + S and GLU (P < 0.05) and on day 35 were greater for CON than G + S (P < 0.05) with intermediate values observed for GLU. The N intake (g/d) between days 0 and 35 was greater for CON than G + S or GLU (P < 0.05) and N retention in combined carcass and viscera was greater for CON than G + S (P < 0.01) with intermediate values observed for GLU. No treatment effects were observed for efficiency of N utilization. Between days 0 and 21 however, the efficiency of using dietary N for N retention in carcass and viscera tended to be less for pigs fed CON vs. GLU (73.8% vs. 91.6%), while intermediate values were observed for G + S (84.3%; P = 0.095). Pigs fed CON and G + S diets had greater skin collagen abundance than pigs fed GLU on days 21 and 35 (P < 0.01). Supplementing low CP diets with Glu or with Gly and Ser at the levels used in the current study did not maintain ADG or combined carcass and viscera N retention and only the G + S diet supported skin collagen abundance not different from pigs fed CON. The importance of meeting essential AA requirements for growth are well accepted, but supplementing specific NEAA may be needed when feeding reduced CP diets to newly weaned pigs to support secondary indicators of AA status, such as skin collagen abundance.


Assuntos
Colágeno/metabolismo , Dieta com Restrição de Proteínas/veterinária , Suplementos Nutricionais , Glicina/farmacologia , Serina/farmacologia , Suínos/crescimento & desenvolvimento , Ração Animal/análise , Animais , Composição Corporal , Dieta/veterinária , Glicina/administração & dosagem , Masculino , Serina/administração & dosagem , Pele/metabolismo , Soja , Suínos/fisiologia
4.
Int J Oral Maxillofac Implants ; 35(35): 197-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923303

RESUMO

PURPOSE: Numerous approaches have been proposed for the treatment of peri-implantitis, but to date, none has been identified as the most effective. This study compared the efficacy of implantoplasty and glycine air polishing for the surgical treatment of peri-implantitis. MATERIALS AND METHODS: This prospective, randomized, parallel-group trial included 31 patients presenting with 42 implants with peri-implantitis. Patients underwent surgical treatment by implantoplasty (test group, n = 22) or glycine air polishing (control group, n = 20). Clinical parameters (Plaque Index), bleeding on probing (BOP), suppuration on probing (SOP), probing pocket depth (PPD), relative attachment level (RAL), and mucosal recession were assessed before surgery (baseline), and at 3 months and 6 months after surgery. Bone loss was recorded at baseline and 6 months. Two composite outcomes were also evaluated, according to the following definitions: (1) mean PPD reduction ≥ 0.5 mm + no further loss of bone; (2) PPD ≤ 5 mm, absence of BOP/SOP, and no additional mean bone loss ≥ 0.5 mm. RESULTS: Plaque Index remained low (< 0.5) in both groups for the duration of the study. Mean BOP, SOP, PPD, and RAL were greatly reduced at 3 months in both groups, and remained low between 3 months and 6 months. Bone loss was stable in the implantoplasty group, and slight bone gain (0.5 mm) was observed in the glycine air-polishing group. There were no significant differences between the two groups in any parameter, and composite treatment outcomes were similar in both groups, irrespective of the definition. CONCLUSION: Within the limitations of this 6-month follow-up study, implantoplasty is as effective as glycine air polishing for the surgical treatment of peri-implantitis.


Assuntos
Abrasão Dental por Ar , Glicina , Peri-Implantite , Seguimentos , Glicina/administração & dosagem , Humanos , Peri-Implantite/cirurgia , Índice Periodontal , Estudos Prospectivos , Resultado do Tratamento
5.
J Environ Sci Health B ; 55(4): 376-381, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31880202

RESUMO

Urochloa decumbens plants may be reached by herbicide drift from applications of glyphosate from neighboring areas or by variations during applications. Considering the different phenological stages and size of plants in these areas, the amount of active ingredient that reaches the plants probably varies. The objective of this study was to evaluate the effects of the application of different doses of glyphosate on U. decumbens plants. Two greenhouse experiments were conducted with two replications at different times. The first experiment evaluated the biological response of U. decumbens plants to glyphosate doses (0, 2.81, 5.63, 11.25, 22.5, 45, 90, 180, 360, 720, and 1,440 g a.e. ha-1), with six replications. The second experiment evaluated the response of U. decumbens plants to the application of a selected low dose of 11.25 g a.e. ha-1. Evaluations of injury were performed at 0, 7, 14, and 21 days after application, and dry weight of plants was determined for each evaluation period. U. decumbens plants increased in dry weight when using the glyphosate dose of 11.25 g a.e. ha-1. However, plants had different responses to the application of this low dose. It can promote both stimulation and inhibition of plant growth.


Assuntos
Glicina/análogos & derivados , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Glicina/farmacologia , Herbicidas/administração & dosagem , Hormese/efeitos dos fármacos , Poaceae/crescimento & desenvolvimento
6.
Fish Shellfish Immunol ; 97: 367-374, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31866449

RESUMO

A total of 180 unsexed Nile Tilapia fish (initial weight, 21 g) fed isonitrogenous (32%), isocaloric (3000 kcal/kg) diets containing different levels of guanidinoacetic acid (GAA) at levels of (GAA1, 0.06%, GAA2, 0.12%, GAA3, 0.18%); for 60 days. Results showed higher final body weight (FBW) and body weight gain (BWG) in groups supplemented with different levels of GAA. Specific growth rate (SGR) was the highest in groups supplemented with 0.12% and 0.18% GAA. Lipid % of whole-body composition was higher in all groups excluding GAA3 group. Serum creatine kinase (CK) activity, cholesterol, and creatinine levels showed a marked significant (P < 0.05) increase in all GAA supplemented groups compared to the control one. Triglycerides level demonstrated a higher elevation (P < 0.05) in both GAA2 and GAA3 supplemented groups. No significant observed in total protein, albumin, globulin, and A/G ratio. Lipid peroxidation marker (malondialdehyde/MDA) is markedly decreased along with a significant increase of superoxide dismutase (SOD), reduced glutathione (GSH), and nitric oxide (NO) levels in both GAA2 and GAA3 compared to other groups. Similarly, interleukin 1ß (IL-1ß) and tumor necrosis factor (TNF-α) gene expression levels were downregulated along with upregulation of transforming growth factor ß1 (TGF-ß1) at higher GAA levels, particularly at 0.18%. Our findings give important insights for the growth promoting, antioxidant and immunomodulatory effects of GAA supplemented diet particularly at level of 0.18%.


Assuntos
Antioxidantes/metabolismo , Ciclídeos/imunologia , Citocinas/imunologia , Glicina/análogos & derivados , Ração Animal/análise , Animais , Ciclídeos/crescimento & desenvolvimento , Ciclídeos/metabolismo , Citocinas/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Glicina/administração & dosagem , Glicina/metabolismo , Distribuição Aleatória
7.
Int J Mol Sci ; 20(18)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540330

RESUMO

Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1G93A mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1G93A mice. The mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) concentration dependently stimulated the release of [3H]d-Aspartate ([3H]d-Asp), which was comparable in 30- and 60-day-old wild type mice and SOD1G93A mice. At variance, [3H]d-Asp release was significantly augmented in 90-day-old SOD1G93A mice and both mGluR1 and mGluR5 were involved. The 3,5-DHPG-induced [3H]d-Asp release was exocytotic, being of vesicular origin and mediated by intra-terminal Ca2+ release. mGluR1 and mGluR5 expression was increased in Glu spinal cord axon terminals of 90-day-old SOD1G93A mice, but not in the whole axon terminal population. Interestingly, mGluR1 and mGluR5 were significantly augmented in total spinal cord tissue already at 60 days. Thus, function and expression of group I mGluRs are enhanced in the early-symptomatic SOD1G93A mouse spinal cord, possibly participating in excessive Glu transmission and supporting their implication in ALS. Please define all abbreviations the first time they appear in the abstract, the main text, and the first figure or table caption.


Assuntos
Esclerose Amiotrófica Lateral/genética , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Superóxido Dismutase-1/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Ácido Glutâmico/metabolismo , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Camundongos , Mutação , Receptor de Glutamato Metabotrópico 5/genética , Receptores de Glutamato Metabotrópico/genética , Resorcinóis/administração & dosagem , Resorcinóis/farmacologia , Medula Espinal/metabolismo , Regulação para Cima
8.
Environ Int ; 132: 105072, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401414

RESUMO

Numerous intentionally released toxins persist in agricultural or natural environments at low concentrations. Such low toxin doses are regularly associated with hormesis, i.e., growth stimulation, and they are suspected to affect mortality and within-population plant size distribution in dense plant stands. However, it is not known whether all these low-dose effects exist when plants grow in soil. We exposed barley to a range of low glyphosate doses and let the plants grow in dense stands for several weeks in soil. Six experiments were done that contained altogether 10,260 seedlings in 572 pots. We evaluated if the changes in average biomass and shoot length occur at the same concentrations as do the effects on slow- and fast-growing individuals, if seed size or early vigor explains variation in the response to glyphosate, and if low toxin doses change within-population mortality. Plant biomass, length and survival of subpopulations changed at doses that did not affect mean biomass. Effects of early vigor faded early, but differences in seed size and particularly vegetative growth had impacts: fast-growing plants hardly showed hormesis, whereas hormesis was particularly strong among slow-growing individuals. Compared to the population mean, glyphosate effects started at lower doses among slow-growing individuals and at higher doses among fast-growing individuals. Several times higher doses were needed before the fast-growing individuals showed the same toxicity as most of the population. Low toxin doses regularly enhanced the growth of the smallest individuals, which reduced size variation within populations and was associated with a higher number of surviving plants. Indeed, in one experiment self-thinning was not observed at low doses that stimulated the growth of slow-growing plants. As glyphosate levels in this study match those observed in agricultural fields and natural environments, we conclude that even low-levels of agro-environmental contamination are likely to shape phenotypic response, which might lead to adaptation and cascading ecological impacts.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Hordeum/efeitos dos fármacos , Hormese , Biomassa , Germinação , Glicina/administração & dosagem , Glicina/toxicidade , Herbicidas/administração & dosagem , Hordeum/crescimento & desenvolvimento , Densidade Demográfica , Sementes/crescimento & desenvolvimento , Solo
10.
Biomed Pharmacother ; 118: 109175, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351423

RESUMO

Increasing research indicates that hyperglycemia plays a crucial role in the progression of diabetic nephropathy (DN); however, effective treatment for preventing or slowing DN progression are seriously lacking. Although salidroside (SAL) has been demonstrated to have a positive anti-diabetic effect, the cellular mechanisms remain unclear. FG-4592, a novel prolyl hydroxylase inhibitor, was used to regulate HIF-1α and HIF-2α expression. The present study aimed to explore the underlying mechanisms of SAL and FG-4592 on high glucose (HG)-induced rat glomerular endothelial cells (rGECs) injury. HG-cultured rGECs were used to induce a diabetic environment. An MTT assay, RT-qPCR, Western blot, flow cytometry, and immunofluorescent staining were performed to investigate the effects of SAL on HG-induced rGECs injury. FG-4592 and SAL protected rGECs against HG-induced injury by increasing cellular viability and reducing the cell apoptosis rate. SAL and FG-4592 downregulated PHD-2 expression and upregulated HIF-1α and HIF-2α expression. In conclusion, our findings suggest that SAL and FG-4592 ameliorate HG-induced rGEC injury by upregulating HIF expression, indicating that SAL and FG-4592 might be favorable for further DN-treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Células Endoteliais/efeitos dos fármacos , Glucose/toxicidade , Glucosídeos/farmacologia , Glicina/análogos & derivados , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Isoquinolinas/farmacologia , Glomérulos Renais/efeitos dos fármacos , Fenóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glucosídeos/administração & dosagem , Glicina/administração & dosagem , Glicina/farmacologia , Isoquinolinas/administração & dosagem , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Fenóis/administração & dosagem , Estabilidade Proteica , Ratos , Regulação para Cima
11.
J Environ Sci Health B ; 54(10): 803-809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264502

RESUMO

The aim of this study was to evaluate the effect of time of the day and their associated climatic conditions on spray deposition of two 2,4-D formulations, as well as the influence on weed control. The experiment was installed in the field in complete randomized design. Treatments were arranged in factorial design 8 × 2, with 20 repetitions. First factor corresponded to different application time (1:00, 4:00, 7:00, 10:00, 13:00, 16:00, 19:00, and 22:00) with their respective climatic conditions. The second factor consisted of two formulations of 2,4-D applied at 776 g a.e. ha-1 (2,4-D amine and 2,4-D choline salt with Colex-D™ Technology) + glyphosate (816 g a.e. ha-1). There was more spray deposition when 2,4-D choline formulation was used, and such differences were more evident for applications performed under adverse climatic conditions. More spray deposition was found in applications performed at times of day with more favorable temperature and humidity of the air conditions. Only the initial control of the evaluated species was affected by the time of application.


Assuntos
Ácido 2,4-Diclorofenoxiacético , Herbicidas , Plantas Daninhas , Controle de Plantas Daninhas/métodos , Ácido 2,4-Diclorofenoxiacético/administração & dosagem , Bidens , Brasil , Cenchrus , Commelina , Glicina/administração & dosagem , Glicina/análogos & derivados , Herbicidas/administração & dosagem , Umidade , Distribuição Aleatória , Temperatura , Tempo (Meteorologia)
12.
Br Poult Sci ; 60(5): 554-563, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31190558

RESUMO

1. Guanidinoacetic acid (GAA) is the single endogenous precursor of creatine, which plays a critical role in energy homeostasis of cells. Since GAA is endogenously converted to creatine by methylation, it was hypothesised that the effects of dietary GAA supplementation might determine the methionine (Met) availability in corn-soybean based diets. 2. A total of 540, one-day-old male Ross 308 broilers were allocated to nine dietary treatments with six replicates (10 birds each) in a 3 × 3 factorial arrangement with three graded levels of supplementary Met (+0.4 g/kg per level), whilst cystine was equal across groups, resulting in a low, medium and high level of total sulphur amino acids, and with three levels of GAA (0, 0.6 and 1.2 g/kg). Birds were fed for 42 days. 3. Increasing levels of supplemental Met enhanced performance indices in all rearing periods, although there was no effect on feed conversion ratio in the grower or feed intake in the finisher periods. Final body weight was 8.8% and 14.6% higher in the birds fed medium and high Met diets, respectively, compared to the low Met level. Relative breast weight and protein content in muscle on d 25 linearly increased with higher levels of Met. At low and high Met levels, growth in the finisher phase was negatively affected by supplementing GAA at 1.2 g/kg. It was suggested that disturbances in methylation homeostasis and/or changes in Arg metabolism might explain these findings. At the end of the grower phase, muscle creatine content was higher when feeding GAA at 0.6 and 1.2 g/kg (4464 and 4472, respectively, vs. 4054 mg/kg fresh muscle in the control group). 4. The effects of dietary GAA supplementation were influenced by the dietary Met level only in the finisher period, which indicates the need for proper sulphur amino acid formulation in diets when feeding GAA.


Assuntos
Galinhas/fisiologia , Glicina/análogos & derivados , Metionina/metabolismo , Músculos Peitorais/fisiologia , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Disponibilidade Biológica , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Suplementos Nutricionais/análise , Metabolismo Energético/efeitos dos fármacos , Glicina/administração & dosagem , Glicina/metabolismo , Masculino , Metionina/administração & dosagem , Tamanho do Órgão/efeitos dos fármacos , Músculos Peitorais/efeitos dos fármacos , Distribuição Aleatória
13.
J Agric Food Chem ; 67(20): 5754-5763, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31045365

RESUMO

Recently, although ginseng ( Panax ginseng C. A. Meyer) and its main component saponins (ginsenosides) have been reported to exert protective effects on cisplatin (CDDP)-induced acute kidney injury (AKI), the beneficial activities of non-saponin on CDDP-induced AKI is little known. This research was designed to explore the protective effect and underlying mechanism of arginyl-fructosyl-glucose (AFG), a major and representative non-saponin component generated during the process of red ginseng, on CDDP-caused AKI. AFG at doses of 40 and 80 mg/kg remarkably reversed CDDP-induced renal dysfunction, accompanied by the decreased levels of serum creatinine and blood urea nitrogen. Interestingly, all of oxidative stress indices were ameliorated after pretreatment with AFG continuously for 10 days. Importantly, AFG relieved CDDP-induced inflammation and apoptosis in part by mitigating the cascade initiation steps of nuclear factor κB signals and regulating the participation of the phosphatidylinositol 3-kinase/protein kinase B signal pathway. In conclusion, these results clearly provide strong rationale for the development of AFG to prevent CDDP-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Arginina/análogos & derivados , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Glucose/administração & dosagem , Glicina/análogos & derivados , NF-kappa B/metabolismo , Panax/química , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Arginina/administração & dosagem , Arginina/química , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/química , Glucose/química , Glicina/administração & dosagem , Glicina/química , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Reação de Maillard , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
14.
Eur J Clin Pharmacol ; 75(8): 1099-1108, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31011758

RESUMO

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.


Assuntos
Antineoplásicos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glicina/análogos & derivados , Itraconazol/farmacologia , Síndrome do QT Longo/epidemiologia , Piridinas/farmacocinética , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas/etnologia , Feminino , Interações Alimento-Droga/etnologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos
15.
Eur J Haematol ; 102(6): 494-503, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30943323

RESUMO

OBJECTIVES: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. METHODS: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. RESULTS: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. CONCLUSIONS: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Qualidade de Vida , Resultado do Tratamento
16.
J Anim Physiol Anim Nutr (Berl) ; 103(3): 766-773, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941826

RESUMO

The objective of this study was to assess the effects of guanidinoacetic acid (GAA) on growth performance, creatine deposition and blood amino acid (AA) profile on broiler chickens. In Exp. 1, a total of 540 one-day-old Arbor Acres male broilers (average initial body weight, 45.23 ± 0.35 g) were divided randomly into five treatments with six replicates of 18 chicks each. Broilers were fed corn-soybean meal-basal diets supplemented with 0, 600, 800, 1,000 or 1,200 mg/kg GAA for 42 days respectively. Results showed that dietary GAA inclusion increased average daily gain (ADG) and improved gain-to-feed ratio (G:F) from 1 to 42 days (p < 0.01). However, average daily feed intake was unaffected by dietary supplementation of GAA. As GAA inclusion increased, the contents of creatine in plasma and kidney were increased (linear, p < 0.01), while the contents of GAA and creatine in liver were decreased (linear, p < 0.01). Similarly, GAA supplementation was inversely related to concentrations of most essential AA in plasma. In Exp. 2, a total of 432 one-day-old Arbor Acres male broilers (average initial body weight, 39.78 ± 0.58 g) were divided randomly into four treatments with six replicates of 18 chicks each. Birds were fed a corn-soybean meal-basal diet supplemented with 0, 200, 400 or 600 mg/kg GAA for 42 days respectively. Dietary inclusion of 600 mg/kg GAA significantly increased ADG and G:F of broilers (p < 0.05). In conclusion, dietary supplementation of 600-1,200 mg/kg GAA can effectively improve the growth performance in broiler chickens by affecting creatine metabolism and utilization efficiency of essential AA, and 600 mg/kg GAA is the minimum dose for improving performance.


Assuntos
Aminoácidos/sangue , Galinhas/crescimento & desenvolvimento , Creatina/metabolismo , Glicina/análogos & derivados , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Galinhas/sangue , Dieta/veterinária , Suplementos Nutricionais , Glicina/administração & dosagem , Glicina/farmacologia , Masculino , Distribuição Aleatória
17.
Psychopharmacology (Berl) ; 236(9): 2623-2633, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30993360

RESUMO

RATIONALE: Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice. OBJECTIVES AND METHODS: Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague-Dawley rats. RESULTS: Synthetic OlGly (1-30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated. CONCLUSION: Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.


Assuntos
Analgésicos Opioides/efeitos adversos , Glicina/análogos & derivados , Morfina/efeitos adversos , Naloxona/toxicidade , Ácidos Oleicos/administração & dosagem , Recompensa , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Glicina/metabolismo , Masculino , Camundongos , Antagonistas de Entorpecentes/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ácidos Oleicos/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-30981909

RESUMO

Roundup® is currently the most widely used and sold agricultural pesticide in the world. The objective of this work was to investigate the effects of Roundup® on energy metabolism during zebrafish (Danio rerio) embryogenesis. The embryo toxicity test was performed for 96 h post-fertilisation and the sublethal concentration of Roundup® was defined as 58.3 mg/L, which resulted in failure to inflate the swim bladder. Biochemical assays were performed with viable embryos following glyphosate exposure, and no significant effects on protein, glucose, glycogen, triglyceride levels or the enzymatic activities of alanine aminotransferase and aspartate aminotransferase were observed. However, the activity of hexokinase was significantly altered following exposure to 11.7 mg/L Roundup®. Through molecular docking we have shown for the first time that the interactions of glucokinase and hexokinases 1 and 2 with glyphosate showed significant interactions in the active sites, corroborating the biochemical results of hexokinase activity in zebrafish exposed to the chemical. From the results of molecular docking interactions carried out on the Zfishglucok, ZfishHK1 and ZfishHK2 models with the glyphosate linker, it can be concluded that there are significant interactions between glyphosate and active sites of glucokinase and hexokinase 1 and 2 proteins. The present work suggests that Roundup® can induce problems in fish embryogenesis relating to the incapacity of swim bladder to inflate. This represents the first study demonstrating the interaction of glyphosate with hexokinase and its isoforms.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicina/análogos & derivados , Peixe-Zebra/embriologia , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucoquinase/metabolismo , Glicina/administração & dosagem , Glicina/toxicidade , Hexoquinase/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica
19.
PLoS Genet ; 15(3): e1007633, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30845140

RESUMO

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan, and early adulthood is important for its salutary effects. Moreover, supplementation of glycine ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, which also feeds into the methionine cycle. RNA-sequencing reveals a similar transcriptional landscape in serine- and glycine-supplemented worms both demarked by widespread gene repression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle.


Assuntos
Caenorhabditis elegans/metabolismo , Glicina/metabolismo , Longevidade/fisiologia , Metionina/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Dieta , Genes de Helmintos , Glicina/administração & dosagem , Longevidade/efeitos dos fármacos , Longevidade/genética , Redes e Vias Metabólicas/genética , Mutação , Interferência de RNA , Serina/administração & dosagem , Serina/metabolismo , Transcriptoma/efeitos dos fármacos
20.
Expert Opin Investig Drugs ; 28(5): 421-433, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907163

RESUMO

INTRODUCTION: Ixazomib is a new, orally administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia (WM). Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone; (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly diagnosed MM following induction therapy and autologous stem cell transplantation; (iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis. Finally, we explore early phase clinical studies of this agent in Waldenström macroglobulinemia. Expert opinion: A key advantage of ixazomib is that it could allow an efficacious treatment approach to MM and other lymphoproliferative disorders through a convenient oral administration route. Ixazomib could soon be used in combination treatment regimens, but more work is necessary to define the place of this agent going forward.


Assuntos
Antineoplásicos/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Transtornos Linfoproliferativos/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Dexametasona/administração & dosagem , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Glicina/administração & dosagem , Glicina/farmacologia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Transtornos Linfoproliferativos/fisiopatologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/fisiopatologia , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacologia , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/fisiopatologia
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