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1.
Medicine (Baltimore) ; 98(40): e16950, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577697

RESUMO

BACKGROUND: Anorexia is a common cause of malnutrition and is associated with negative effects on the quality of life (QOL) for patients with cancer. Management of appetite is the key to improving both the QOL and the prognosis for such patients. Yukgunja-tang (YGJT) is a traditional herbal medicine extensively prescribed in Korea as a remedy for various gastrointestinal syndromes. Currently, no standardized herbal medicine treatment exists for patients with cancer who are suffering from anorexia after surgery, chemotherapy, and/or radiotherapy. For that reason, this study aims to examine the efficacy and the safety of using YGJT to treat anorexia in such patients and to establish whether or not YGJT can be recommended as the primary therapy. METHODS: We will enroll 52 cancer patients diagnosed with anorexia. The enrolled participants will be randomly allocated to 2 groups: The control group will receive nutrition counseling, and the YGJT group will receive nutrition counseling and be administered YGJT at a dose of 3 g twice a day for 4 weeks (a total of 56 doses of 3.0 g per dose). The primary outcome of this study is the change in the score on the anorexia/cachexia subscale (A/CS) of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT). The secondary outcomes are the changes in the FAACT score with the A/CS score excluded, the score on the Visual Analogue Scale (VAS) for appetite, the weight and the body mass index (BMI), and laboratory tests for compounds such as leptin, tumor necrosis factor-α (TNF-α), ghrelin, and IL-6. All variables related to the safety assessment, such as vital signs, electrocardiography results, laboratory test results (CBC, chemistry, urine test), and adverse events, will be documented on the case report form (CRF) at every visit. CONCLUSION: This study is the first randomized controlled trial to investigate the efficacy and the safety of using YGJT for treating patients with cancer-related anorexia in Korea. We designed this study based on previous research about YGJT. This study will serve as a pilot and provide data for planning further clinical trials on herbal medicine and cancer-related anorexia. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, ID: KCT0002847. Registered retrospectively on 3 April 2018.


Assuntos
Anorexia/tratamento farmacológico , Anorexia/etiologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Apetite , Índice de Massa Corporal , Peso Corporal , Método Duplo-Cego , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Qualidade de Vida , República da Coreia , Projetos de Pesquisa , Adulto Jovem
2.
Nutrients ; 11(6)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208031

RESUMO

BACKGROUND: During activity-based anorexia (ABA) in mice, enhanced paracellular permeability and reduced protein synthesis have been shown in the colon while the gut-brain axis has received increasing attention in the regulation of intestinal and mood disorders that frequently occur during anorexia nervosa, a severe eating disorder for which there is no specific treatment. In the present study, we assessed the effects of oral glutamine (Gln) or branched-chain amino acids (BCAA) supplementation during ABA to target intestinal functions, body composition and feeding behavior. METHODS: C57BL/6 male mice were randomized in Control (CTRL) and ABA groups. After ABA induction, mice received, or not, either 1% Gln or 2.5% BCAA (Leu, Ile, Val) for one week in drinking water. RESULTS: Neither Gln nor BCAA supplementation affected body weight and body composition, while only Gln supplementation slightly increased food intake. ABA mice exhibited increased paracellular permeability and reduced protein synthesis in the colonic mucosa. Oral Gln restored colonic paracellular permeability and protein synthesis and increased the mucin-2 mRNA level, whereas BCAA did not affect colonic parameters. CONCLUSION: In conclusion, oral Gln specifically improves colonic response during ABA. These data should be further confirmed in AN patients.


Assuntos
Aminoácidos de Cadeia Ramificada/farmacologia , Anorexia/tratamento farmacológico , Suplementos Nutricionais , Glutamina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Animais , Anorexia/fisiopatologia , Composição Corporal/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/fisiopatologia , Comportamento Alimentar/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos
3.
Neuropeptides ; 75: 58-64, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948035

RESUMO

Reduced appetite or anorexia substantially deteriorates quality of life in various diseases including cancer, depression and heart failure. Furthermore, reduced appetite may stand upstream of sarcopenia and frailty. All these diseases are heavy burdens in the modern medicine and society. Therefore, the means that counteracts reduced appetite has been awaited, however, effective and well evidenced substance is not currently available. Ninjin-yoeito, a Japanese kampo medicine comprising twelve herbs has been used to treat anorexia. However, underlying mechanism is little known. Neuropeptide Y (NPY) and ghrelin are the most potent central and peripheral inducers of appetite, respectively. This study sought to determine whether Ninjin-yoeito influences NPY and/or ghrelin-responsive neurons in the hypothalamic arcuate nucleus (ARC), a feeding center. We isolated single neurons from ARC of mice and measured cytosolic Ca2+ concentration ([Ca2+]i) with fura-2 fluorescence imaging, followed by immunocytochemical identification of NPY neurons. Ninjin-yoeito (1-10 µg/ml) increased [Ca2+]i in ARC neurons, the majority (80%) of which was immunoreactive to NPY. One fraction of these Ninjin-yoeito-responsive NPY neurons also responded to ghrelin, while another fraction did not. Furthermore, oral administration of Ninjin-yoeito (1 g/kg/day) counteracted the reductions in food intake and body weight by cisplatin, an anti-cancer drug, in mice. These results demonstrate that Ninjin-yoeito directly targets both ghrelin-responsive and unresponsive NPY neurons in ARC and preserves food intake and body weight in cisplatin-treated anorectic mice. Ninjin-yoeito's signaling through ghrelin-responsive and ghrelin-unresponsive NPY pathways may provide strong mechanistic basis for this medicine for treating anorectic conditions associated with cancer, depression, heart failure, sarcopenia, frailty and aging.


Assuntos
Anorexia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Grelina/metabolismo , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Animais , Anorexia/induzido quimicamente , Núcleo Arqueado do Hipotálamo/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Camundongos , Neurônios/metabolismo
4.
Pediatr Blood Cancer ; 66(6): e27676, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30786157

RESUMO

BACKGROUND: Melatonin is a natural health product used for sleep disturbances. In preliminary studies of adults with advanced cancer, 20 mg of melatonin daily was associated with reduction in anorexia and weight loss-symptoms that also impact pediatric oncology patients. High doses of melatonin have not been studied in pediatrics. METHODS: This was a multicenter single-arm phase I dose-escalation study utilizing a 3 + 3 design to determine the safety and tolerability of escalating doses of melatonin in pediatric oncology patients with relapsed solid tumors. Melatonin was given for 8 weeks at three dose levels-0.075 mg/kg (maximum 5 mg), 0.15 mg/kg (maximum 10 mg), and 0.3 mg/kg (maximum 20 mg). RESULTS: Melatonin was well tolerated at all three dose levels with no significant adverse events or dose-limiting toxicities. The only grade 3/4 toxicities were myelosuppression, which was attributed to the concomitant chemotherapy and occurred at all dose levels. Weight gain occurred in seven of nine patients, with a median increase of 1.1 kg (range -3.3 to 4.5) or 3.4% (range -10.2 to 8.7), with two patients losing weight (one in dose level 1 and one level 3). CONCLUSIONS: Melatonin is well tolerated at a dose of 0.3 mg/kg (maximum 20 mg), in the pediatric population. This study provides the background for further study of high-dose melatonin in pediatric oncology patients.


Assuntos
Anorexia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Neoplasias/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adolescente , Anorexia/induzido quimicamente , Anorexia/diagnóstico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Neoplasias/patologia , Prognóstico , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/diagnóstico
5.
Integr Cancer Ther ; 18: 1534735419828832, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789014

RESUMO

Cisplatin induces anorexia, weight loss, loss of adipose tissue, skeletal muscle atrophy, and serious adverse effects that can cause premature termination of chemotherapy. The aim of this study was to use an animal model to assess cisplatin therapy (3 cycles) with and without d-methionine to investigate its protective effects on cisplatin-induced anorexia and skeletal muscle wasting. Wistar rats were divided into 3 groups and treated as follows: saline as control (group 1), intraperitoneal cisplatin once a week for 3 weeks (group 2), and intraperitoneal cisplatin once a week for 3 weeks plus oral administration of d-methionine (group 3). Tissue somatic index (TSI), gastric emptying index (GEI), and feeding efficiency were measured. Both hepatic lipid metabolism and muscle atrophy-related gene expressions and C2C12 myotubes were determined by polymerase chain reaction. Micro-computed tomography (micro-CT) was used to conduct assessment of bone microarchitecture indices. Pathological changes of the gastric mucosa were assessed by hematoxylin and eosin staining after euthanizing the animals. d-Methionine increased food intake, weight gain, gastric emptying, and feeding efficiency, as well as decrease stomach contents, after cisplatin injections. Cisplatin caused shortening of myofibers. Cisplatin-induced muscle mass wasting was mediated by the elevation of mRNA expressions of MAFbx and MuRF-1 in ubiquitin ligases in muscle tissue homogenate. The mRNA expressions of MyoD and myogenin, markers of muscle differentiation, declined following cisplatin administration. The administration of d-methionine not only led to significant improvements in myofiber diameter and cross-sectional fiber areas but also reversed muscle atrophy-related gene expression. However, there were no significant changes in stomach histology or microarchitecture of trabecular bone among the study groups. The results indicate that d-methionine has an appetite-enhancing effect and ameliorates cisplatin-induced adipose and muscle tissue loss during cisplatin-based chemotherapy.


Assuntos
Cisplatino/efeitos adversos , Cisplatino/farmacologia , Metionina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Animais , Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Linhagem Celular , Masculino , Camundongos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Perda de Peso/efeitos dos fármacos
6.
Neurosci Res ; 143: 53-60, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29879461

RESUMO

The most common side effects of the cancer chemotherapy drug cisplatin are nausea and vomiting. These effects are heavily influenced by orexigenic and anorexigenic peptides. We explored the effects of orexin-A on the cisplatin-treated rats and a possible mechanism for its effects on cisplatin-induced side effects. Quantitative real-time PCR was used to measure the change of prepro-orexin mRNA in the hypothalamus following cisplatin treatment. The effect of orexin-A and cisplatin on the firing rate of arcuate nucleus neurons was recorded. The effect of administration of orexin-A and a neuropeptide Y1 receptor antagonist to the arcuate nucleus on food intake, pica, and gastric motility on cisplatin treated rats were also measured. The relative expression of prepro-orexin mRNA in the hypothalamus was reduced by cisplatin. Exogenous orexin-A altered cisplatin-induced changes to the neuronal firing of gastric distension-responsive neurons, alleviated the cisplatin-induced anorexia, pica and improves the weakened gastric motility in the arcuate nucleus of rats. These effects could be partially blocked by intracerebroventricular injection (i.c.v.) of a neuropeptide Y1 receptor antagonist. These results suggest that orexin-A signaling ameliorates the gastric disorder induced by cisplatin in rats, and may act through neuropeptide Y neurons in the arcuate nucleus.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Cisplatino/farmacologia , Orexinas/farmacologia , Estômago/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Anorexia/tratamento farmacológico , Núcleo Arqueado do Hipotálamo/metabolismo , Arginina/análogos & derivados , Arginina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Infusões Intraventriculares , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Orexinas/genética , Orexinas/metabolismo , Pica/tratamento farmacológico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Estômago/inervação
7.
Yakugaku Zasshi ; 138(9): 1169-1179, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30175761

RESUMO

 In patients with cancer, it is difficult to continue medical treatment owing to nausea and vomiting (NV). Therefore, it is important to avoid these problems for improving the patient's QOL. Rikkunshito extract (RK) possesses antiemetic effects and is used in combination in cancer therapy. However, patients with cancer find it difficult to take the medicine orally for the treatment of NV and anorexia owing to the characteristic smell and taste of traditional Chinese medicine. We examined the pharmaceutical properties of RK suppository for hospital use, assessed bioequivalence by using pharmacokinetic parameters, and determined its effectiveness against NV and anorexia in rats. In this study, RK suppository was prepared by using RK formulation (A, B, and C) and Witepsol (H and S) (AH, BH, CH, AS, BS, and CS). Pharmaceutical properties, namely, hardness, dispersibility, long-term stability, and drug (hesperidin and glycyrrhizic acid) release were measured for AH, BH, AH, and AS. The pharmacokinetic parameters, effectiveness of substance P against NV and anorexia, and serotonin-activated ghrelin levels were assessed for BH only. AH, BH, AS, and AS demonstrated uniform and sufficient hardness. The release rate of oleaginous components, such as glycyrrhizic acid, did not change significantly, while that of water soluble components, such as hesperidin, decreased when compared with that in powder formulations A and B. NV and anorexia improved in rats administered BH compared with the control group. BH suppository showed effectiveness in terms of both physicochemical property and bioequivalence for hospital use.


Assuntos
Anorexia/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Animais , Antieméticos , Fenômenos Químicos , Modelos Animais de Doenças , Esquema de Medicação , Composição de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Ratos Wistar , Supositórios , Equivalência Terapêutica , Resultado do Tratamento
8.
Int J Eat Disord ; 51(8): 1020-1025, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102796

RESUMO

OBJECTIVE: This study tested the effects of ketamine on vulnerability of female adolescent mice to activity-based anorexia (ABA). METHOD: Twenty-four female C57Bl/6 J mice underwent ABA induction, which involved exposing wheel-acclimated adolescent mice to two bouts of food restriction (FR)-the first ABA (P41-44, mid-adolescence) and the second ABA (P55-59, late adolescence), with recovery in between. Ketamine (3 or 30 mg/kg) or vehicle was given once, on the second day of FR of the first ABA (P42). Food consumption, body weight and wheel running activity were measured daily. Anxiety-like behaviors were accessed by elevated plus maze on P49 and P62, after weight restoration during the recovery phase. RESULTS: Ketamine (30 mg/kg) increased food intake during the first ABA (+38%, p = .015) and facilitated weight gain during recovery (+42%, p = .003). During the second ABA, the effect was manifested as increased food intake (+38%, p = .001) and weight gain (+47%, p = .001) while attenuating FR-induced wheel running activity (-24%, p = .09) and weight loss (-17%, p = .056). Ketamine also reduced anxiety-like behaviors. DISCUSSION: Thus, single injection of ketamine during mid-adolescence effectively attenuates vulnerability of female mice to repeated ABA exposures.


Assuntos
Analgésicos/uso terapêutico , Anorexia/tratamento farmacológico , Ansiedade/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Ketamina/uso terapêutico , Adolescente , Analgésicos/farmacologia , Animais , Anorexia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Ketamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Trends Endocrinol Metab ; 29(8): 560-570, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29866502

RESUMO

Growth differentiation factor-15 (GDF15) is a circulating protein that has been implicated in multiple biological processes, including energy homeostasis, body weight regulation, and cachexia driven by cancer and chronic disease. The potential to target GDF15 in the treatment of energy-intake disorders, including obesity and anorexia, is an area of intense investigation, but has been limited by the lack of an identified receptor, signaling mechanism, and target tissue. GDNF family receptor α-like (GFRAL) was recently identified as the neuronal brainstem receptor responsible for mediating the anorectic actions of GDF15. Herein, we provide a brief overview of GDF15 biology with a focus on energy homeostasis, and highlight the implications of the recent receptor identification to this field and beyond.


Assuntos
Anorexia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial , Fator 15 de Diferenciação de Crescimento , Obesidade , Animais , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator 15 de Diferenciação de Crescimento/agonistas , Fator 15 de Diferenciação de Crescimento/antagonistas & inibidores , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo
10.
J Pharmacol Exp Ther ; 366(3): 422-432, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29914876

RESUMO

Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.


Assuntos
Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Grelina/análogos & derivados , Grelina/farmacologia , Lipopolissacarídeos/efeitos adversos , Sequência de Aminoácidos , Animais , Anorexia/metabolismo , Anorexia/fisiopatologia , Ligação Competitiva , Ingestão de Alimentos/efeitos dos fármacos , Grelina/metabolismo , Grelina/farmacocinética , Hormônio do Crescimento/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estabilidade Proteica , Receptores de Grelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , beta-Lactamases/metabolismo
12.
Physiol Behav ; 192: 17-22, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29510158

RESUMO

Glucagon-like peptide 1 (GLP-1) neurons of the caudal brainstem project to many brain areas, including the lateral septum (LS), which has a known role in stress responses. Previously, we showed that endogenous GLP-1 in the LS plays a physiologic role in the control of feeding under non-stressed conditions, however, central GLP-1 is also involved in behavioral and endocrine responses to stress. Here, we asked whether LS GLP-1 receptors (GLP-1R) contribute to stress-induced hypophagia. Male rats were implanted with bilateral cannulas targeting the dorsal subregion of the LS (dLS). In a within-subjects design, shortly before the onset of the dark phase, rats received dLS injections of saline or the GLP-1R antagonist Exendin (9-39) (Ex9) prior to 30 min restraint stress. Food intake was measured continuously for the next 20 h. The stress-induced hypophagia observed within the first 30 min of dark was not influenced by Ex9 pretreatment, but Ex9 tended to blunt the effect of stress as early as 1 and 2 h into the dark phase. By 4-6 h, there were significant stress X drug interactions, and Ex9 pretreatment blocked the stress-induced suppression of feeding. These effects were mediated entirely through changes in average meal size; stress suppressed meal size while dLS Ex9 attenuated this effect. Using a similar design, we examined the role of dLS GLP-1R in the neuroendocrine response to acute restraint stress. As expected, stress potently increased serum corticosterone, but blockade of dLS GLP-1Rs did not affect this response. Together, these data show that endogenous GLP-1 action in the dLS plays a role in some but not all of the physiologic responses to acute stress.


Assuntos
Ingestão de Alimentos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Septo do Cérebro/metabolismo , Estresse Psicológico/metabolismo , Animais , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Fármacos do Sistema Nervoso Central/farmacologia , Corticosterona/metabolismo , Estudos Cross-Over , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos Wistar , Restrição Física/fisiologia , Restrição Física/psicologia
13.
J Cachexia Sarcopenia Muscle ; 9(3): 444-452, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29542279

RESUMO

In 1993, megestrol acetate (MA) was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome. The mechanism by which MA increases appetite is unknown, and its effectiveness for anorexia and cachexia in neoplastic, elderly, and acquired immunodeficiency syndrome patients is under investigation. This is an updated version of a Cochrane systematic review first published in 2005 and later updated in 2013 entitled 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. MA vs. placebo: in studies where MA was compared with placebo, the overall results showed that MA patients gained weight (mean difference, MD 2.25 kg, 95% CI [1.19, 3.3]) but did not gain quality of life (QOL) (standarized mean difference, SMD 0.5, 95% CI [-0.13, 1.13]), with more adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]), but no difference in deaths (RR 1.26, 95% CI [0.70, 2.27]). MA vs. no treatment: MA patients gained weight (MD 1.45 kg, 95% CI [0.15, 2.75]) but did not gain QOL (standardized mean difference 3.89 95% CI [-14, 6.28]). There was no increase in adverse events (RR 0.90, 95% CI [0.39, 2.08]) or deaths (RR 1.01, 95% CI [0.42, 2.45]). MA vs. active drugs: MA patients gained weight (MD 2.5 kg, 95% CI [0.37, 4.64]) but did not gain QOL (MD 0.20 95% CI [-0.02, 0.43]) and did not report an increase in adverse events (RR 1.05 95% CI [0.95, 1.16]) or in deaths (RR 1.53, 95% CI [1.02, 2.29]) Different doses of MA: in studies where lower doses of MA were compared with higher doses of MA, we did not find differences either in weight gain (MD -0.94 kg, 95% CI [-3.33, 1.45]), QOL (MD 0.31 95% CI [-0.19, 0.81]), or adverse events (RR 1.34, 95% CI [0.65, 2.76]). Thus, we cannot reach a conclusion for an optimal dose of MA.


Assuntos
Anorexia/tratamento farmacológico , Estimulantes do Apetite/uso terapêutico , Caquexia/tratamento farmacológico , Acetato de Megestrol/uso terapêutico , Anorexia/etiologia , Anorexia/mortalidade , Estimulantes do Apetite/farmacologia , Caquexia/etiologia , Caquexia/mortalidade , Humanos , Acetato de Megestrol/farmacologia , Prognóstico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome , Resultado do Tratamento
14.
Support Care Cancer ; 26(7): 2479-2489, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29442239

RESUMO

PURPOSE: Previous studies reported promising efficacy for celecoxib in the treatment of cancer cachexia. We designed this study to test the hypothesis that combination therapy with megestrol acetate (MA) plus celecoxib is superior to MA alone. METHODS: Ninety eligible gastrointestinal cancer patients randomly received either MA 320 mg/day plus placebo (arm1) or MA 320 mg/day plus celecoxib 200 mg/day (arm2). Patients were evaluated at baseline, then 1 and 2 months after starting interventions. The primary outcome was body weight. Secondary outcomes were quality of life, grip strength, appetite score, performance status, plasma albumin, CRP, IL-6, and Glasgow Prognostic Score. RESULTS: Patients were comparable at baseline. Sixty patients were assessable for the first month and 33 patients for the second month. After 2 months, patients in arm1 (MA + placebo) and arm2 (MA + celecoxib) experienced 4.0 ± 3.4 and 2.2 ± 3.6Kg of weight gain respectively (P = 0.163). Changes relative to baseline were statistically significant in both arms of the study (P = 0.001). Regarding secondary outcomes, comparisons between groups did not show any statistically significant difference, but within-group changes were significant in both arms of the study. CONCLUSION: Since both MA alone and MA plus celecoxib are associated with improvement of cachexia in GI cancer patients, this study failed to show that adding celecoxib (200 mg/day) to megestrol (320 mg/day) could enhance anti-cachexic effects of megestrol.


Assuntos
Anorexia/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Caquexia/tratamento farmacológico , Celecoxib/uso terapêutico , Terapia Combinada/métodos , Neoplasias Gastrointestinais/complicações , Acetato de Megestrol/uso terapêutico , Qualidade de Vida/psicologia , Antineoplásicos Hormonais/farmacologia , Celecoxib/farmacologia , Método Duplo-Cego , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Acetato de Megestrol/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , Ganho de Peso
15.
Eur J Pharmacol ; 818: 148-157, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29066414

RESUMO

Despite its therapeutic advantages, chemotherapy with anti-cancer drugs can cause adverse effects, including anorexia and weight loss. Although most patients with cancer suffer from anorexia during chemotherapy, resulting in the need to suspend or cease treatment and thereby worsening prognosis, treatment options for anorexia remain limited. Ghrelin is an orexigenic hormone that has been proposed to prevent anorexia. To investigate the potential of ghrelin receptor agonists, synthetic small-molecule compounds, as preventive therapies for chemotherapy-induced anorexia, we studied the effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, in cisplatin- and 5-fluorouracil (5-FU)-induced anorexia animal models. The agonistic activity of Z-505 was examined using calcium flux assays in Chinese hamster ovary (CHO-K1) cells stably expressing rat or mouse GHSR1a. Z-505 showed agonistic activity for rat GHSR1a and mouse GHSR1a, with a half maximal effective concentration (EC50) of 2.08nM and 5.46nM, respectively. In a cisplatin-induced anorexia rat model, administration of Z-505 (30, 100 or 300mg/kg, p.o., once daily) significantly improved the cisplatin-induced reduction in food intake and body weight. In addition, treatment with Z-505 (100 or 300mg/kg, p.o., once daily) prevented the 5-FU-induced decrease in food intake and body weight in the 5-FU-induced mouse model. Our results demonstrate that Z-505 ameliorates cisplatin- and 5-FU-induced anorexia through the activation of the ghrelin receptor, GHSR1a, suggesting its usefulness in the preventive treatment of anorexia during chemotherapy.


Assuntos
Amidas/farmacologia , Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Pirrolidinas/farmacologia , Receptores de Grelina/metabolismo , Amidas/uso terapêutico , Animais , Anorexia/metabolismo , Anorexia/fisiopatologia , Peso Corporal/efeitos dos fármacos , Células CHO , Cisplatino/efeitos adversos , Cricetinae , Cricetulus , Ingestão de Alimentos/efeitos dos fármacos , Fluoruracila/efeitos adversos , Camundongos , Pirrolidinas/uso terapêutico , Ratos
16.
Mol Med Rep ; 17(2): 2665-2672, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29207134

RESUMO

Chemotherapy frequently causes anorexia in cancer patients, which has been associated with poor disease prognosis. Several therapeutic strategies for the treatment of chemotherapy­induced anorexia are available; however, their adverse effects limit their clinical use. Herbal medicines have a long history of use for the treatment of various diseases, including cancer, and recent research has demonstrated their safety and efficacy. In the present study, combinations of herbal medicines were designed based on traditional Korean medicine, and their effects were investigated on chemotherapy­induced anorexia. Herbal mixtures were extracted, composed of Atractylodes japonica, Angelica gigas, Astragalus membranaceus, Lonicera japonica Thunb., Taraxacum platycarpum H. Dahlstedt and Prunella vulgaris var. asiatica (Nakai) Hara. The mixtures were termed LCBP­Anocure­16001­3 (LA16001, LA16002, LA16003). A cisplatin­induced anorexic mouse model was used to evaluate the putative effects of the extracts on chemotherapy­induced anorexia. Treatment with LA16001 was revealed to prevent body weight loss, and all three extracts were demonstrated to improve food intake. When the molecular mechanisms underlying the orexigenic effects of LA16001 were investigated, altered expression levels of ghrelin, leptin and interleukin­6 were revealed. Furthermore, LA16001 was reported to induce phosphorylation of Janus kinase 1 and signal transducer and activator of transcription 3. In addition, LA16001 administration increased the number of white blood cells and neutrophils. These results suggested that the herbal formula LA16001 may be able to prevent chemotherapy­induced anorexia and may have potential as a novel therapeutic strategy for the adjuvant treatment of patients with cancer.


Assuntos
Anorexia/etiologia , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Extratos Vegetais/farmacologia , Animais , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Apetite/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Medicina Herbária , Hormônios/metabolismo , Humanos , Janus Quinase 1/metabolismo , Masculino , Camundongos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Neuropharmacology ; 131: 282-290, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29247677

RESUMO

The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS. Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex-9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS. Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls. Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia.


Assuntos
Anorexia/metabolismo , Tronco Encefálico/metabolismo , Caquexia/metabolismo , Carcinoma Hepatocelular/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Animais , Anorexia/tratamento farmacológico , Anorexia/patologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/patologia , Caquexia/tratamento farmacológico , Caquexia/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Fármacos do Sistema Nervoso Central/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Técnicas de Silenciamento de Genes , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Masculino , Transplante de Neoplasias , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Endogâmicos BUF , Síndrome , Perda de Peso/efeitos dos fármacos , Perda de Peso/fisiologia
18.
Medwave ; 17(9): e7130, 2017 Dec 29.
Artigo em Espanhol, Inglês | MEDLINE | ID: mdl-29286357

RESUMO

INTRODUCTION: Cachexia and anorexia are among the most frequent symptoms in patients with cancer. Cannabinoids have been used in patients with advanced cancer; however, their role is still controversial. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified ten systematic reviews including three studies overall, of which two were randomized trials. We concluded it is not clear whether cannabinoids have any positive effect on increasing weight because the certainty of the evidence is very low. They might not have any effect on appetite, and are probably associated to frequent adverse effects.


Assuntos
Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Canabinoides/uso terapêutico , Anorexia/etiologia , Apetite/efeitos dos fármacos , Caquexia/etiologia , Canabinoides/efeitos adversos , Bases de Dados Factuais , Humanos , Neoplasias/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome , Resultado do Tratamento
19.
PLoS One ; 12(11): e0187804, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29155861

RESUMO

BACKGROUND: Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF. AIM: We attempted to detect the association between PEI and CHF-induced appetite. METHODS: Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study. RESULTS: The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels (r = 0.694, p < 0.001). Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 µg/g stool and SNAQ < 14. CONCLUSIONS: Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms.


Assuntos
Anorexia/fisiopatologia , Apetite/efeitos dos fármacos , Insuficiência Pancreática Exócrina/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Adulto , Idoso , Anorexia/complicações , Anorexia/tratamento farmacológico , Apetite/fisiologia , Índice de Massa Corporal , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/tratamento farmacológico , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Extratos Pancreáticos/administração & dosagem , Albumina Sérica/metabolismo , Inquéritos e Questionários , Função Ventricular Esquerda/fisiologia
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