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Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal function, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic efficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Kampo , Acetilcolinesterase , Animais , Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Donepezila , Medicamentos de Ervas Chinesas/uso terapêutico , Grelina , Humanos , Caulim/efeitos adversos , Camundongos , Náusea/induzido quimicamente , Pica/induzido quimicamente , Receptores de Grelina , Vômito/induzido quimicamenteRESUMO
BACKGROUND AND AIM: Functional dyspepsia (FD) is characterized by chronic and unexplained indigestion at upper abdomen. Because of unsatisfactory effect of conventional treatments, demand is growing for complementary and alternative medicine. Rikkunshito (RKT) is a herbal medicine, which has been widely used for FD in Asia; however, the evidence is lacking. We carried out systematic review and meta-analysis to evaluate the effect and safety of RKT in the treatment of FD. METHODS: Electronic databases were searched in April 2019, including PUBMED, EMBASE, and Cochrane Library. All eligible studies should be randomized controlled trials (RCTs) comparing RKT or combination therapy (RKT and western medicine) group to western medicine group. The primary outcome measure was the total clinical efficacy rate (TCE). The secondary outcomes were total dyspepsia symptom scale, gastric emptying rate, gastrin, motilin, recurrence 6 months after treatment, and Hamilton depression rating scale. RESULTS: Fifty-two RCTs with 5475 patients were involved in this systematic review and meta-analysis. Compared with western medicine, RKT showed significant better result, with higher TCE (relative risk = 1.21, 95% confidence interval 1.17 to 1.25, P < 0.001). RKT presented higher reduction of total dyspepsia symptom scale, more improved gastric emptying rate, and lower recurrence 6 months after treatment compared with western medicine. However, there was no significant difference in Hamilton depression rating scale between RKT and western medicine group. Combination therapy brought significant symptom improvement with TCE compared with western medicine alone. CONCLUSIONS: Rikkunshito and combination therapy might be considered an effective alternative treatment for FD. Further rigorously designed and high-quality RCTs are needed.
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Medicamentos de Ervas Chinesas/uso terapêutico , Dispepsia/tratamento farmacológico , Fitoterapia , Quimioterapia Combinada , Dispepsia/etiologia , Feminino , Esvaziamento Gástrico , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Rikkunshito has been used to treat gastrointestinal (GI) disorders. The purpose of this study was to investigate the effects of Rikkunshito, a traditional Japanese herbal medicine, on the pacemaker potentials of interstitial cells of Cajal (ICCs) from the small intestines of mice. METHODS: We isolated ICCs from the small intestines of mice, and the whole-cell patch-clamp configuration was used to record the pacemaker potentials in cultured ICCs and membrane currents. RESULTS: Rikkunshito depolarized ICC pacemaker potentials in a dose-dependent manner. Pretreatment with GSK1614343 or (D-Lys3)-growth hormone-releasing peptide-6 inhibited Rikkunshito-induced depolarization of pacemaker potentials. Intracellular GDP-ß-S inhibited Rikkunshito-induced effects. In Ca2+-free solution or in the presence of thapsigargin, Rikkunshito did not depolarize pacemaker potentials. Moreover, in the presence of U-73122 or xestospongin C, Rikkunshito-induced effects were inhibited. However, in the presence of staurosporine, Go6976 or Rottlerin, Rikkunshito depolarized pacemaker potentials. Furthermore, Rikkunshito inhibited both transient receptor potentials melastatin 7 (TRPM7) and Ca2+-activated Cl- channels (ANO1) currents. CONCLUSION: Rikkunshito depolarized pacemaker potentials of ICCs via ghrelin receptor and G protein through internal or external Ca2+-, phospholipase C-, and inositol triphosphate-dependent and protein kinase C-, TRPM7-, and ANO1-independent pathways. The study shows that Rikkunshito may alleviate GI motility disorders through its depolarizing effects on ICCs.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Células Intersticiais de Cajal/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Receptores de Grelina/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Motilidade Gastrointestinal/fisiologia , Células Intersticiais de Cajal/fisiologia , Intestino Delgado/citologia , Intestino Delgado/fisiologia , Camundongos , Técnicas de Patch-Clamp , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacosRESUMO
Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.
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Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Ovarianas/metabolismo , Receptores de Grelina/efeitos dos fármacos , Sirtuína 1/efeitos dos fármacos , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Caderinas/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Grelina/efeitos dos fármacos , Grelina/metabolismo , Humanos , Neoplasias Ovarianas/genética , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Vimentina/efeitos dos fármacos , Vimentina/metabolismoRESUMO
Teriparatide is clinically used for the treatment of osteoporosis; however, nausea is often observed in patients. Its insufficient control affects the ability to continue teriparatide therapy. Rikkunshi-To (RKT), a traditional Japanese herbal medicine, improves the gastrointestinal function via activation of the ghrelin-signaling system. We investigated the therapeutic effects of RKT on teriparatide-induced nausea in rats and the involvement of ghrelin in these effects. We previously reported that ovariectomized rats showed pica (kaolin ingestion), a behavior that can be used to assess nausea in rats, after the subcutaneous administration of teriparatide; thus, the behavior was used as an index of nausea. Ovariectomized rats were fed diets with or without RKT (1%) for 2 weeks, and then they received the subcutaneous injection of teriparatide (400 µg/kg). Teriparatide significantly increased the incidence of pica, while suppressing intestinal motility and plasma ghrelin levels in rats fed normal diets; however, rats fed diets with RKT showed improvements in all of the teriparatide-induced adverse reactions. These therapeutic effects were antagonized by a ghrelin receptor antagonist ([D-Lys3]-GHRP-6; 200 nmol/rat). These findings suggest that the enhancement of ghrelin-signaling is involved in RKT's therapeutic effect, and that RKT is a potentially useful treatment for teriparatide-induced nausea.
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Conservadores da Densidade Óssea/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Grelina/fisiologia , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Fitoterapia , Pica/induzido quimicamente , Pica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Teriparatida/efeitos adversos , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/sangue , Injeções Subcutâneas , Ovariectomia , Ratos Wistar , Teriparatida/administração & dosagemRESUMO
Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR.
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Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Caquexia/complicações , Caquexia/tratamento farmacológico , Restrição Calórica , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/efeitos dos fármacos , Animais , Atrofia , Caquexia/genética , Caquexia/patologia , Tamanho Celular/efeitos dos fármacos , DNA Mitocondrial/genética , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/genética , Neoplasias/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Nus , Ratos WistarRESUMO
BACKGROUND: Patients with Parkinson's disease (PD) usually experience distress related not only to motor dysfunction, but also to nonmotor symptoms, including gastrointestinal dysfunction. OBJECTIVE: The purpose of this pilot study was to evaluate the efficacy and safety profile of a traditional Japanese medicine, rikkunshito (RKT), used for the treatment of gastrointestinal symptoms, associated with anorexia and dyspepsia, in patients with PD. METHODS: Patients were randomly assigned to either Group A (4-week treatment period with 7.5 g/d RKT followed by a 4-week off-treatment period) or Group B (4-week off-treatment period followed by a 4-week treatment period with 7.5 g/d RKT). Appetite, quality of life for gastrointestinal symptoms, and depression were assessed using a visual analog scale, the Gastrointestinal Symptom Rating Scale and the Self-Rating Depression Scale, respectively. The gastric emptying examination and assay of plasma acylated ghrelin level were performed using the 13C-acetate breath test and commercially available assay kits, respectively. RESULTS: RKT treatment produced a significant increase in the appetite score (1.84 [2.34]; P < 0.05), compared to a decrease in the score over the off-treatment period (-1.36 [2.94]). The mean score for abdominal pain, on the Gastrointestinal Symptom Rating Scale, and for self-reported depression, on the Self-Rating Depression Scale, also decreased significantly with RKT treatment (P < 0.05), compared with the off-treatment period scores. No effect of RKT on plasma acylated ghrelin level and rate of gastric emptying was identified. CONCLUSIONS: RKT may improve anorexia in patients with PD. The positive effects of RKT on depression and anorexia may improve the overall quality of life of these patients. The benefits of RKT identified in our pilot study will need to be confirmed in a randomized, double-blind, controlled trial. UMIN Clinical Trial Registry identifier: UMIN000009626.
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BACKGROUND: Only a few reports focused on esophageal motility in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) and there has been no established strategy for treatment. OBJECTIVE: To clarify the characteristics of esophageal motility in patients with PPI-refractory NERD, we evaluated esophageal function using combined multichannel intraluminal impedance and esophageal manometry (MII-EM). In addition, we evaluated the efficacy of rikkunshito (RKT), which is a gastrointestinal prokinetic agent. METHODS: Thirty patients with NERD were enrolled and underwent MII-EM. After 8 weeks of RKT (7.5 g/d) treatment, MII-EM was repeated on patients with PPI-refractory NERD. Symptoms were assessed by the Gastrointestinal Symptom Rating Scale. RESULTS: In patients with PPI-refractory NERD, measures of complete bolus transit, peristaltic contractions, and residual pressure of the lower esophageal sphincter during swallowing deviated from the standard values and esophageal clearance was found to be deteriorated. RKT significantly improved the peristaltic contractions (P < 0.05), the complete bolus transit (P < 0.01), and the residual pressure of lower esophageal sphincter (P < 0.05) in these patients. The overall score (P < 0.01) and the subscale scores of acid reflux syndrome (P < 0.05), abdominal pain (P < 0.05), and indigestion syndrome (P < 0.01) in the Gastrointestinal Symptom Rating Scale were significantly improved by the 8-week RKT treatment. CONCLUSIONS: In the pilot study, patients with PPI-refractory NERD had disorders of esophageal and lower esophageal sphincter motility that were improved by RKT. Further studies examining esophageal motor activity of RKT in PPI-refractory NERD are required. University hospital Medical Information Network (UMIN) Clinical Trial Registry identifier: UMIN000003092.
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We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6-8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.
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BACKGROUND: After esophagectomy, esophageal cancer patients suffer from malnutrition, anorexia, and dysfunction of digestion and absorption. Rikkunshito, a traditional Japanese herbal medicine, reportedly attenuates gastrointestinal symptoms and appetite loss after gastrointestinal surgery. We evaluated the clinical effect of rikkunshito and its relationship with ghrelin in esophageal cancer patients after esophagectomy. METHODS: This prospective nonrandomized study included 40 patients with esophageal cancer who underwent esophagectomy at Wakayama Medical University Hospital. They were assigned to either the control group (n = 20, April 2011-January 2012) or the rikkunshito group (n = 20, January 2012-August 2012). Patients in the rikkunshito group received 2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after surgery. During the 48-week treatment, we assessed body weight loss, nutritional parameters, and quality of life (Functional Assessment of Cancer Therapy-Esophageal scale). The primary end point was the rate of body weight loss in two groups after the 48-week treatments. RESULTS: The rate of body weight loss was significantly less in the rikkunshito group than in the control group (P = 0.016). The acyl ghrelin level after the 48-week treatments was significantly higher in the rikkunshito group (131.7% ± 74.5%) than in the control group (75.6% ± 47.5%, P = 0.039). For the Functional Assessment of Cancer Therapy-Esophageal symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P = 0.031). CONCLUSIONS: For esophageal cancer patients after esophagectomy, rikkunshito is useful for improving body weight loss in connection with an increase in plasma acyl ghrelin levels.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Fármacos Gastrointestinais/farmacologia , Desnutrição/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Redução de Peso/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Esquema de Medicação , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Grelina/sangue , Humanos , Masculino , Desnutrição/sangue , Desnutrição/etiologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) in infants is among the most common reason for physician consultation worldwide. A traditional Japanese medicine, rikkunshito (RKT), is effective for GERD in adult and pediatric patients. The aim of this study was to evaluate the efficacy and safety of RKT in infants with GERD. METHODS: Fifty-four infants were referred to between July 2004 and December 2012 for evaluation and treatment of GERD. All infants had failure to thrive. We excluded nine patients with cow's milk protein allergy, neurological impairment or surgical indications. We retrospectively reviewed the clinical records of 45 infants with GERD. Twenty-nine infants were treated with RKT (TJ-43; 0.3 g/kg/day; RKT group), and 16 infants were treated with mosapride citrate at 0.5 mg/kg/day (mosapride group). The primary endpoint was RKT-induced relief of clinical symptoms and bodyweight gain in infants with GERD. RESULTS: After 3 months of treatment, the frequency of vomiting per day was significantly lower in the RKT group than in the mosapride group (P = 0.0146) and the weight Z-score was significantly higher in the RKT group than in the mosapride group (RKT group, -2.5 ± 1.5 vs mosapride group, -5.0 ± 2.0; P = 0.0386). No adverse effects were noted in either group. CONCLUSIONS: RKT may be safe and effective for relief of GER symptoms and for bodyweight gain in infants with GERD.
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Medicamentos de Ervas Chinesas , Refluxo Gastroesofágico/terapia , Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Acute lung injury (ALI) is a critical syndrome consisting of acute respiratory failure associated with extensive pulmonary infiltrates. The pathological characterization of ALI includes injuries of alveolar epithelial cells (AECs), alveolar neutrophilic infiltration, and increases in proinflammatory cytokines, which cause destruction of the alveolar capillary barrier and subsequent devastating lung fibrosis. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment of patients with gastrointestinal symptoms and is known to stimulate ghrelin secretion. The therapeutic effects of RKT on organ inflammation and fibrosis remain unknown. We investigated the pharmacological potential of RKT in the treatment of ALI by using a bleomycin-induced ALI model in mice. RKT or distilled water (DW) was given to mice daily starting 12 h after bleomycin administration. The RKT-treated mice showed a definitively higher survival rate than the DW-treated mice after injury. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of AECs, and subsequent lung fibrosis were notable in the RKT-treated mice. RKT administration increased the plasma ghrelin levels in wild-type mice, and it also mitigated the ALI response in both ghrelin-deficient mice and growth hormone secretagogue receptor-deficient mice after lung injury. Our results indicate that RKT administration exerts protective effects against ALI by protecting the AECs and regulating lung inflammation independently of the ghrelin system, and they highlight RKT as a promising therapeutic agent for the management of this intractable disease.
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Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Grelina/deficiência , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Bleomicina , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Grelina/sangue , Grelina/metabolismo , Ácido Glicirrízico/farmacologia , Hesperidina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Infiltração de Neutrófilos/efeitos dos fármacos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC.
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Caquexia/etiologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Neoplasias Gástricas/complicações , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Citocinas/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hormônios Hipotalâmicos/genética , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Masculino , Melaninas/genética , Melaninas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Consumo de Oxigênio , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Nus , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
Objective The effect of Rikkunshito, a Japanese herbal Kampo medicine, on chemotherapy-induced nausea and vomiting (CINV) has been evaluated in several small prospective studies, with mixed results. We retrospectively evaluated the antiemetic effects of Rikkunshito in patients undergoing cisplatin-based chemotherapy using a large-scale database in Japan. Methods The Diagnosis Procedure Combination inpatient database from July 2010 to March 2019 was used to compare adult patients with malignant tumors who had received Rikkunshito on or before the day of cisplatin administration (Rikkunshito group) and those who had not (control group). Antiemetics on days 2 and 3 and days 4 and beyond following cisplatin administration were used as surrogate outcomes for CINV. Patient backgrounds were adjusted using the stabilized inverse probability of treatment weighting, and outcomes were compared using univariable regression models. Results We identified 669 and 123,378 patients in the Rikkunshito and control groups, respectively. There were significantly fewer patients using intravenous 5-HT3-receptor antagonists in the Rikkunshito group (odds ratio, 0.38; 95% confidence interval, 0.16-0.87; p=0.023) on days 2 and 3 of cisplatin-based chemotherapy. Conclusion The reduced use of antiemetics on day 2 and beyond of cisplatin administration suggested a beneficial effect of Rikkunshito in palliating the symptoms of CINV.
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Antieméticos , Antineoplásicos , Medicamentos de Ervas Chinesas , Adulto , Humanos , Antieméticos/uso terapêutico , Antieméticos/efeitos adversos , Cisplatino/uso terapêutico , Japão , Medicina Kampo , Estudos Prospectivos , Estudos Retrospectivos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
INTRODUCTION: Myocardial ischemia/reperfusion (I/R) injury can cause additional damage to an ischemic myocardium, even after successful reperfusion therapy. Inflammation is a mechanism that exacerbates myocardial damage after I/R injury. Rikkunshito (RKT) is a traditional Japanese herbal medicine widely used to treat gastrointestinal symptoms. It attenuates inflammation and fibrosis in some diseases of the heart; however, it remains unclear whether RKT exerts cardioprotective effects against myocardial I/R injury. To elucidate this, we evaluated the effects of RKT pre-treatment by oral administration on the myocardium in a mouse model of in vivo I/R injury. METHODS: Mice were randomly assigned to a group receiving distilled water (DW) or one receiving RKT (1000 mg/kg/day) for 14 days orally. For each of the RKT and DW groups, a sham group, an I/R 2 h group, and an I/R 24 h group were created. On day 15, myocardial I/R surgery was performed. The left anterior descending coronary artery (LAD) was ligated for 30 min, and reperfusion time was set at 2 h or 24 h. The myocardial infarct size (IS) was measured after 2 h of reperfusion, and cardiac cytokine mRNA expression levels were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR) after 2 h and 24 h of reperfusion. RESULTS: RKT pre-treatment significantly suppressed the cardiac mRNA expression level of interleukin-1ß in the RKT-I/R 2 h group compared to the DW-I/R 2 h group (P < 0.05). Additionally, RKT significantly suppressed the mRNA expression levels of transforming growth factor-ß compared to DW; the same result was obtained for the expression levels of interleukin-6. However, RKT did not reduce the IS or mRNA expression levels of the cardiac congestive markers natriuretic peptide a (NPPA) and natriuretic peptide b (NPPB). In addition, RKT did not alter the plasma concentration of ghrelin and sirtuin 1 (Sirt1), which have been reported to be stimulated by RKT. CONCLUSION: This study showed that pre-treatment of RKT for myocardial I/R injury partially suppressed inflammation-related cytokines. However, further studies are needed on the effect of RKT on the reduction of myocardial infarction size.
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BACKGROUND: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW. METHODS: We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats. KEY RESULTS: RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys3]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys3]-GHRP-6. CONCLUSIONS & INFERENCES: RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW.
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BACKGROUND: The loss of the gastroesophageal junction after proximal gastrectomy (PG) induces various gastrointestinal symptoms, such as regurgitation, anorexia, and body weight loss, leading to impairment of the postoperative quality of life. In the present study, we investigated the long-term quality of life and the effects of rikkunshito, a traditional Japanese medicine (kampo), on the gastrointestinal symptoms and plasma ghrelin levels in patients with gastric cancer who had undergone PG. METHODS: Nineteen patients who had undergone PG> 6 mo before entry into the present study were enrolled. The plasma ghrelin levels, body weight, appetite, and Gastrointestinal Symptom Rating Scale (GSRS) scores were examined before and after the 4-wk administration of rikkunshito. A subgroup analysis was performed of patients showing a GSRS score of ≥ 2 before treatment, indicating the presence of gastrointestinal symptoms. RESULTS: The patients' body weight increased significantly after the administration of rikkunshito. Neither their appetite nor plasma acylated and deacylated ghrelin levels were significantly affected. In the subgroup analysis, the mean total GSRS score improved significantly from 2.6 ± 0.6 before the administration of rikkunshito to 1.9 ± 0.7 after administration because of the significant improvement in the subscale scores for abdominal pain, acid reflux, diarrhea, and constipation. CONCLUSIONS: The long-term quality of life was well preserved in the patients who had undergone PG at our hospital. In the patients with a baseline GSRS score of ≥2, rikkunshito significantly improved the symptoms of postgastrectomy syndrome, and its effect was possibly independent of the plasma ghrelin levels.
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Medicamentos de Ervas Chinesas/administração & dosagem , Gastrectomia/efeitos adversos , Medicina Kampo/métodos , Síndromes Pós-Gastrectomia/tratamento farmacológico , Qualidade de Vida , Neoplasias Gástricas/cirurgia , Idoso , Apetite/efeitos dos fármacos , Feminino , Gastrectomia/métodos , Grelina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Redução de Peso/efeitos dos fármacosRESUMO
The herbal medicine Yukgunja-tang has been widely used for the treatment of functional dyspepsia (FD) in the clinical setting of East Asian traditional medicine. This paper presents a protocol for a randomized, assessor-blind, controlled, multicenter, three-arm parallel clinical trial comparing the effectiveness, safety, and cost-effectiveness of Yukgunja-tang with Pyeongwi-san and usual care. A total of 140 participants with Rome IV-diagnosed FD will be randomly assigned to either the Yukgunja-tang (n = 56), Pyeongwi-san (n = 56), or usual care (n = 28) groups. All participants will be educated on dietary guidelines for FD patients. Participants in the Yukgunja-tang and Pyeongwi-san groups will take investigational products for 6 weeks. All participants will be assessed for clinical parameters at weeks 0, 3, 6, 9, and 24. The primary outcome will be measured on the total dyspepsia symptom scale, and the secondary outcome will include the single dyspepsia symptom scale, overall treatment effect, the visual analog scale for dyspepsia, FD-related quality of life, hospital anxiety and depression scale, EuroQol-5 dimension, pattern identification, and serum levels of acyl-ghrelin and deacyl-ghrelin. Adverse events and laboratory tests will be monitored for safety assessment. The results will provide evidence of the effectiveness, safety, and cost-effectiveness of Yukgunja-tang in the treatment of FD.
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BACKGROUND: Yukgunja-tang (YGJ) is an herbal prescription used to treat the symptoms of gastroesophageal reflux disease (GERD). Although many preclinical and clinical studies on YGJ have been conducted on GERD, there is a lack of evidence from blinded studies to exclude placebo effects. Therefore, this protocol proposes a clinical trial that is single-centered, randomized, double-blinded, double-dummy to objectively evaluate the efficacy and safety of co-administered YGJ and rabeprazole (RPZ) in patients with GERD previously treated with proton pump inhibitors (PPIs) and still experiencing symptoms. METHODS: A total of 86 participants with refractory GERD (rGERD) will be randomized in a 1:1 ratio to the treatment [YGJ and RPZ (10 mg/d)] and control groups [double-dose RPZ (20 mg/d)] for 4 weeks of treatment (weeks 0-4) followed by 4 weeks of follow-up (weeks 4-8). The Frequency Scale for the Symptoms of GERD will be analyzed for the primary endpoint. Reflux Disease Questionnaire, Reflux Symptom Score, GERD-Health Related Quality of Life, Overall Treatment Evaluation, Spleen Qi Deficiency Questionnaire, Damum Questionnaire, and dyspepsia Visual Analogue Scale will be used to evaluate treatment effects on GERD related symptoms and quality of life and to compare treatment effects by subgroups. Safety tests will be analyzed by investigating adverse events. DISCUSSION: This clinical trial will be the first rigorous double-blind, double-dummy, placebo-controlled study to precisely evaluate the efficacy and safety of the combination of YGJ and PPIs in the treatment of rGERD. The results of this study will provide a reliable clinical basis for selecting botanical drug treatments for patients with rGERD. TRIAL REGISTRATION: Clinical Research Information Service (registration number: KCT0008600, July 13, 2023, https://cris.nih.go.kr ).
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Refluxo Gastroesofágico , Inibidores da Bomba de Prótons , Humanos , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Qualidade de Vida , Rabeprazol/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Método Duplo-CegoRESUMO
BACKGROUND: Although rikkunshito was reported to be effective for treatment-resistant nonerosive gastroesophageal reflux disease (NERD), it is unclear which Rome IV subgroups of NERD patients benefit fromrikkunshito. This study investigated the efficacy of rikkunshito in patients with functional heartburn. METHODS: Ten patients with functional heartburn who experienced symptoms of dyspepsia were enrolled and received rikkunshito for 8 weeks. The Frequency Scale for Symptoms of GERD (FSSG), the Japanese translation of the Quality of Life in Reflux and Dyspepsia (QOLRAD-J) questionnaire, and the Hospital Anxiety and Depression Scale (HADS) before, and 4 and 8 weeks after, administration were evaluated. Overall treatment efficacy (OTE) was evaluated at 8 weeks after administration. RESULTS: One patient voluntarily withdrew from treatment at 4 weeks. Total FSSG score was significantly (P = 0.039) lower 8 weeks after treatment or at discontinuation (13.2 ± 8.0) than before treatment (18.3 ± 10.7). Although QOLRAD-J score was higher 8 weeks after treatment or at discontinuation than before treatment, the difference was not significant different. HADS score was not significantly lower 8 weeks after treatment or at discontinuation, as compared with before treatment. However, total FSSG and HADS anxiety scores were positively correlated (correlation coefficient: 0.684, P = 0.027). CONCLUSIONS: The findings from this first study of the efficacy of rikkunshito for functional heartburn suggest that it might be effective in such patients.