RESUMO
Constipation is a prevalent gastrointestinal (GI) problem affecting a large number of individuals. This study aimed to investigate peristalsis-promoting potential characteristics of Ligilactobacillus acidipiscis YJ5 and the underlying molecular mechanism. The study demonstrated the relieving effect of L. acidipiscis YJ5 on constipation in both zebrafish and mouse models. L. acidipiscis YJ5 intervention significantly increased intestinal peristalsis by reducing the peak time and increasing the fluorescence disappearance rate in the zebrafish model. In the mouse model, the symptoms of constipation relief induced by L. acidipiscis YJ5 included a shortened first black stool time, an increased number of defecation particles, an accelerated propulsion rate of the small intestine, and an increase in fecal water content. L. acidipiscis YJ5 was found to reduce the expression of colonic aquaporins to normalize the colonic water transport system of constipated mice. Additionally, L. acidipiscis YJ5 reversed loperamide-induced morphological damage in the ileum and colon and increased the colonic mucosal barrier. The results of the 16S rRNA gene analysis indicated that L. acidipiscis YJ5 could reverse the structure of gut microbiota to a near-normal group, including levels of ß-diversity, phylum, family, and genus. Furthermore, the fermentation supernatant of L. acidipiscis YJ5 was shown to relieve constipation, and metabolomics analysis revealed that these positive effects were related to its metabolites like malic acid and heliangin.
Assuntos
Microbioma Gastrointestinal, Peixe-Zebra, Camundongos, Animais, RNA Ribossômico 16S/genética, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/induzido quimicamente, Água/farmacologiaRESUMO
CONTEXT: Constipation is a common problem among patients with cancer. By some accounts, about 60% of cancer patients experience constipation. There is limited empirical evidence of the clinical effectiveness of pharmacologic agents in opioid-induced constipation in advanced diseases. OBJECTIVES: We sought to quantitatively summarize the therapeutic effectiveness of the pharmacologic means of managing opioid-induced constipation. METHODS: Randomized control trials (RCTs) identified from medical literature databases that reported quantitative measures of the effect of pharmacotherapeutic agents to treat opioid induced constipation in patients with cancers and other advanced illnesses were included in this study. A conventional random effects meta-analysis was conducted including >3 trials with the same exposure and outcome assessed, and a network-meta-analysis was conducted for all placebo-controlled trials. RESULTS: Eighteen studies that examined the effect of various pharmacotherapeutic agents were included. The medications were Methylnatrexone (N = 5), Naldemedine (N = 5), other conventional agents (N = 4) and herbal medicines (N = 4). In conventional meta-analysis, methylnaltrexone increased the proportion achieving rescue-free laxation by 2.68 fold (95% CI: 1.34, 5.37; P = 0.0054) within 4 hours of the administration compared to placebo. In network meta-analysis, the pooled RR of the pharmacotherapeutic agents on rescue-free bowel movements as 2.26 (95% CI: 1.52, 3.36) for methylnaltrexone, 1.58 (95% CI: 0.94, 2.66) for naldemedine, and 0.74 (95% CI: 0.45, 1.23) for polyethylene glycol, compared to placebo. CONCLUSION: Methylnatrexone and Naldemedine have currently shown promise in randomized trials concerning opioid-induced constipation in cancer and advanced illness. It is imperative that future research ascertain not just the relative therapeutic efficacy but also the cost-benefit analyses of these newer regimens with more commonly used and accessible laxatives.
Assuntos
Naltrexona/análogos & derivados, Neoplasias, Constipação Induzida por Opioides, Humanos, Constipação Induzida por Opioides/tratamento farmacológico, Antagonistas de Entorpecentes/uso terapêutico, Analgésicos Opioides/efeitos adversos, Naltrexona/uso terapêutico, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Laxantes/uso terapêutico, Neoplasias/complicações, Neoplasias/tratamento farmacológico, Ensaios Clínicos Controlados Aleatórios como Assunto, Compostos de Amônio QuaternárioRESUMO
INTRODUCTION: Peripherally acting µ-opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort. METHODS: This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system. RESULTS: Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% (N = 27) were documented as having a bowel movement, 62% (N = 45) did not have a bowel movement. Reported adverse events were minimal with nausea (N = 3), vomiting (N = 1), and flatulence (N = 6). CONCLUSION: Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.
Assuntos
Naltrexona/análogos & derivados, Neoplasias, Constipação Induzida por Opioides, Adulto, Humanos, Criança, Analgésicos Opioides/efeitos adversos, Constipação Induzida por Opioides/tratamento farmacológico, Estudos Retrospectivos, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Antagonistas de Entorpecentes/efeitos adversos, Neoplasias/tratamento farmacológico, Compostos de Amônio QuaternárioRESUMO
OBJECTIVES: This meta-analysis evaluated the effect of opioids on constipation in ICU patients. REVIEW METHOD USED: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang DATA databases. REVIEW METHODS: Random or fixed-effects meta-analyses were used. Subgroup analysis was performed according to the definition of constipation (three vs. six days), opioids (fentanyl vs. morphine), study design (prospective vs. retrospective), adjustment of confounders (No vs. Yes), and patient's age (adults vs. children). We used sensitivity analysis to test the robustness of results with significant statistical heterogeneity. RESULTS: Seven studies (2264 patients) were included. Opioid use in ICU patients was associated with an increased risk of constipation (relative risk [RR]=1.14; 95% confidence interval [CI]=1.05 to 1.24; I2=49.8%). Subgroup analysis further showed that adjustment form, category of opioid, study design, and patient's age significantly influenced the relationship between opioid use and the risk of constipation. Sensitivity analysis confirmed the robustness of pooled results. CONCLUSION: Opioids significantly increase the risk of constipation in critically ill patients, especially children. It is worth noting that the adjustment of the constipation definition used for ICU significantly influenced the relationship between opioid use and the risk of constipation. Therefore, It is necessary to clearly define ICU constipation and conduct time-based layered treatment. Additional prospective studies are needed to investigate the consistent definition of ICU constipation.
Assuntos
Analgésicos Opioides, Estado Terminal, Adulto, Criança, Humanos, Analgésicos Opioides/efeitos adversos, Estudos Prospectivos, Estudos Retrospectivos, Constipação Intestinal/induzido quimicamenteRESUMO
CONTEXT: Hydromorphone and morphine are the common drugs used for the treatment of moderate to severe cancer pain. Patient controlled subcutaneous analgesia (PCSA) is an effective technique to manage cancer pain. However, few studies have been conducted to show the efficacy and safety of PCSA of hydromorphone for the relief of cancer pain. OBJECTIVES: To explore the short-term efficacy and safety of PCSA elicited by hydromorphone for moderate to severe cancer pain. METHODS: This was a single-center, randomized, active-controlled, double-blind trial (from April 2019 to August 2021). Sixty patients with moderate to severe cancer pain were randomized (1:1) to hydromorphone or morphine groups according to drug delivery by PCSA. The primary outcome was the pain intensity measured by a numerical rating scale (NRS) at 72 hours. Secondary outcomes included pain intensity measured by NRS at baseline, 15 minutes, 30 minutes, two hours, eight hours, 24 hours and 48 hours. The daily occurrence of breakthrough pain (BTP), impact of pain on quality of life measured by the brief pain inventory (BPI), the daily additional consumption of opioids and the incidence of adverse events were also recorded. Adverse events included nausea, vomiting, dizziness, constipation and respiratory depression. RESULTS: A total of 57 patients (28 patients in the hydromorphone group and 29 patients in the morphine group) in the West China Hospital of Sichuan University were investigated. The mean (standard deviation [SD]) NRS in the two groups at baseline was 7.8 (1.7) in the hydromorphone group and 7.6 (1.7) in the morphine group, and at 72 hours were 3.4 (1.8) and 3.2 (1.5), respectively. The postoperative NRS in both groups was decreased significantly compared to baseline. The mean (SD) NRS at 30 minutes in the hydromorphone group was significantly lower than in the morphine group (3.9 [2.6] vs. 5.3 [2.1], P = 0.035). The daily occurrence of BTP in both groups at 48 hours and 72 hours decreased significantly compared to the corresponding baseline (P < 0.05), and there was no significant difference between the two groups. The total scores and sub-item scores of BPI at 24 hours and 72 hours after PCSA in both groups decreased significantly from baseline. A comparison of daily additional consumption of opioids between the two groups revealed no statistically significant difference. There were no significant differences in the incidences of nausea, vomiting, dizziness or constipation between the two groups (P > 0.05). CONCLUSION: This study found that the PCSA of both hydromorphone and morphine could effectively and safely relieve short-term moderate to severe cancer pain. Of note, the PCSA of hydromorphone took effect more quickly than that of morphine.
Assuntos
Dor do Câncer, Neoplasias, Humanos, Hidromorfona/uso terapêutico, Morfina, Dor do Câncer/tratamento farmacológico, Dor do Câncer/complicações, Tontura, Qualidade de Vida, Dor/tratamento farmacológico, Analgésicos Opioides, Analgesia Controlada pelo Paciente, Vômito, Náusea/tratamento farmacológico, Constipação Intestinal/induzido quimicamente, Método Duplo-Cego, Dor Pós-Operatória, Resultado do Tratamento, Neoplasias/complicações, Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period. METHODS: We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran-Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period. RESULTS: Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period. CONCLUSIONS: Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.
Assuntos
Antipsicóticos, Dibenzotiepinas, Metotrimeprazina/análogos & derivados, Esquizofrenia, Humanos, Feminino, Laxantes/efeitos adversos, Esquizofrenia/tratamento farmacológico, Olanzapina/uso terapêutico, Estudos Retrospectivos, Fumarato de Quetiapina/uso terapêutico, Antipsicóticos/efeitos adversos, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológicoRESUMO
BACKGROUND: Dietary approaches are recommended for the management of chronic constipation. Until now, there has been no systematic review and meta-analysis on foods, drinks and diets in constipation. AIMS: To investigate the effect of foods, drinks and diets on response to treatment, stool output, gut transit time, symptoms, quality of life, adverse events and compliance in adults with chronic constipation via a systematic review and meta-analysis. METHODS: Studies were identified using electronic databases (12th July 2023). Intervention trials (randomised controlled trials [RCTs], non-randomised, uncontrolled) were included. Risk of bias was assessed using Cochrane 2.0 (RCTs) or JBI Critical Appraisal (uncontrolled trials). Data from RCTs only were synthesised using risk ratios (RRs), mean differences (MDs), standardised mean differences (95% CI) using random-effects. RESULTS: We included 23 studies (17 RCTs, 6 uncontrolled; 1714 participants): kiwifruit (n = 7), high-mineral water (n = 4), prunes (n = 2), rye bread (n = 2), mango, fig, cereal, oat bran, yoghurt, water supplementation, prune juice, high-fibre diet, no-fibre diet (n = 1). Fruits resulted in higher stool frequency than psyllium (MD: +0.36 bowel movements [BM]/week, [0.25-0.48], n = 232), kiwifruits in particular (MD: +0.36 BM/week, [0.24-0.48], n = 192); there was no difference for prunes compared with psyllium. Rye bread resulted in higher stool frequency than white bread (MD: +0.43 BM/week, [0.03-0.83], n = 48). High-mineral water resulted in higher response to treatment than low-mineral water (RR: 1.47, [1.20-1.81], n = 539). CONCLUSIONS: Fruits and rye bread may improve certain constipation-related outcomes. There is a scarcity of evidence on foods, drinks and diets in constipation and further RCTs are needed.
Assuntos
Águas Minerais, Psyllium, Adulto, Humanos, Constipação Intestinal/induzido quimicamente, Fibras na Dieta, DietaRESUMO
SCOPE: People suffer from constipation caused by many factors, including constipation (Opioid-Induced Constipation, OIC) during analgesic treatment. Microorganisms may be a potent solution to this problem, but the mechanism is still unclear. METHODS AND RESULTS: Based on models in vivo and in vitro, the potential mechanism involving Bifidobacterium animalis F1-7 (B. animalis F1-7), screened in the previous studies, is explored through non-targeted metabonomics, electrophysiological experiment and molecular level docking. The results showed that B. animalis F1-7 effectively alleviates OIC and promotes the expression of chromogranin A (CGA) and 5-hydroxytryptamine (5-HT). The metabolite 13,14-dihydro-15-keto-PGE2 related to B. animalis F1-7 is found, which has a potential improvement effect on OIC at 20 mg kg BW-1 in vivo. At 30 ng mL-1 it effectively stimulates secretion of CGA/5-HT (408.95 ± 1.18 ng mL-1 ) by PC-12 cells and changes the membrane potential potassium ion current without affecting the sodium ion current in vitro. It upregulates the target of free fatty acid receptor-4 protein(FFAR4/ß-actin, 0.81 ± 0.02). CONCLUSION: The results demonstrate that metabolite 13,14-dihydro-15-keto-PGE2 participated in B. animalis F1-7 to alleviate OIC via the 5-HT pathway.
Assuntos
Bifidobacterium animalis, Dinoprostona/análogos & derivados, Constipação Induzida por Opioides, Humanos, Serotonina, Analgésicos Opioides, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológicoRESUMO
We sought to explore the protective effect of the combination of fenchone (FE) and sodium hyaluronate (SH) on ice water-induced IBS-C rats and the potential mechanism. The neurotransmitter levels, including substance P (SP), motilin (MTL), 5-hydroxytryptamine (5-HT), and vasoactive intestinal peptide (VIP), were determined by ELISA methods. The stem cell factors (SCF)/c-Kit signaling pathway-related protein and mRNA levels were determined by western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses, respectively. The expressions of tight ZO-1, Occludin, and Claudin-1 were also measured by western blot assay and immunofluorescence staining. The 16S rRNA gene sequence was used to measure the composition of gut microbiota. The co-administration of FE and SH improved the body weight, number of fecal pellets, fecal moisture, abdominal with drawal reflex score, and gastrointestinal transit rate in IBS-C rats. The unique efficacy of combination depended on the regulation of balance between excitatory and inhibitory neurotransmitters, enhancement of intestinal barrier function, and activation of SCF/c-Kit pathway. The gut microbiota structure was also restored. The ability of FE combined with SH to regulate SCF/c-Kit signaling pathway, enhance intestinal barrier function, and modulate gut microbiota contributes to their efficacy in managing IBS-C in rats.
Assuntos
Canfanos, Síndrome do Intestino Irritável, Norbornanos, Ratos, Animais, Síndrome do Intestino Irritável/tratamento farmacológico, Ácido Hialurônico/efeitos adversos, RNA Ribossômico 16S, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/induzido quimicamenteRESUMO
PURPOSE: Naloxegol has been shown to be an efficient alternative to treat opioid-induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors. METHODS: This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described. RESULTS: A total of 17 254 naloxegol users were identified across the countries. Their median age was 56-71 years, and each country had a majority of women (ranging 57.5%-62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%-90.9% of users, typically during the first 30 days. Approximately 10%-30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation. CONCLUSION: The present study reflects real-world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.
Assuntos
Morfinanos, Polietilenoglicóis, Idoso, Feminino, Humanos, Pessoa de Meia-Idade, Analgésicos Opioides/efeitos adversos, Estudos de Coortes, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/epidemiologia, Laxantes/efeitos adversos, Morfinanos/efeitos adversos, Polietilenoglicóis/efeitos adversos, MasculinoRESUMO
Constipation is directly related to the intestinal microenvironment, in which the promotion of gastrointestinal (GI) motility and improvement of gut microbiota distribution are important for alleviating symptoms. Herein, after the intervention of probiotic fermented milk (FMMIX) containing Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 for 14 d in Kunming mice with loperamide-induced constipation, the results indicated that FMMIX significantly increased the secretion of serum motilin, gastrin and 5-hydroxytryptamine, as well as decreased the secretion of peptide YY, vasoactive intestinal peptide, and nitric oxide in mice. As determined by immunohistochemical analysis, FMMIX promoted an augmentation in the quantity of Cajal interstitial cells. In addition, the mRNA and protein expression of c-kit and stem cell factor (SCF) were upregulated to facilitate intestinal motility. High-throughput sequencing and gas chromatography techniques revealed that FMMIX led to an increase in the relative abundance of beneficial bacteria (Lactobacillus, Oscillospira, Ruminococcus, Coprococcus, and Akkermansia), reduced the presence of harmful bacteria (Prevotella), and resulted in elevated levels of short-chain fatty acids (SCFA) with a superior improvement compared with unfermented milk. Untargeted metabolomics revealed significant upregulation of functional metabolites such as l-pipecolinic acid, dl-phenylalanine, and naringenin in FMMIX, presumably playing a potential role in constipation relief. Overall, our results showed that FMMIX had the potential to alleviate constipation symptoms in mice by improving the secretion of serum GI regulatory peptides and neurotransmitters, increasing the expression of c-kit and SCF proteins, and modulating the gut microbiota structure and SCFA levels, and may be associated with an increase in these functional metabolites. This suggested that FMMIX could be a promising adjunctive strategy for managing constipation symptoms and could contribute to the development of functional foods aimed at improving gut health.
Assuntos
Microbioma Gastrointestinal, Lacticaseibacillus paracasei, Lactobacillus gasseri, Probióticos, Camundongos, Animais, Leite, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/terapia, Constipação Intestinal/veterinária, Motilidade Gastrointestinal, Probióticos/uso terapêutico, Probióticos/farmacologiaRESUMO
Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.
Assuntos
Antagonistas de Entorpecentes, Constipação Induzida por Opioides, Humanos, Antagonistas de Entorpecentes/uso terapêutico, Analgésicos Opioides/efeitos adversos, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/metabolismo, Constipação Induzida por Opioides/tratamento farmacológico, Disbiose/induzido quimicamente, Disbiose/tratamento farmacológico, Receptores Opioides/metabolismoRESUMO
Naldemedine is indicated for the treatment of opioid-induced constipation (OIC), but reports on its efficacy in preventing OIC are few. Therefore, we retrospectively investigated factors affecting the efficacy of concurrent prescription of naldemedine on OIC. Outpatients with cancer who were started on oxycodone 10 mg/d were included in the study. The eligible patients were classified by their physicians into the following three groups: Group A used regular laxatives before the introduction of oxycodone and initiated naldemedine treatment simultaneously with oxycodone administration, Group B did not take laxatives before the introduction of oxycodone and started naldemedine simultaneously with oxycodone administration, and Group C had been administering regular laxatives before the introduction of oxycodone and were not prescribed naldemedine simultaneously with oxycodone treatment. The Support Team Assessment Schedule Japanese edition score for constipation, frequency of defecation, Bristol Stool Form Scale, sense of incomplete rectal evacuation, and development or worsening of straining to pass bowel movements were compared among the three groups before and after oxycodone administration. In Group B, there was significant worsening of the four parameters except for the sense of incomplete rectal evacuation, whereas Groups A and C did not present any changes. In logistic regression analysis, body weight ≥51.8 kg was a factor significantly decreasing the preventive effect of naldemedine on OIC, and regular use of laxatives was a factor significantly increasing the preventive effect of naldemedine on OIC. Thus, the initiation of naldemedine should be considered depending on the body weight and regular laxative use.
Assuntos
Constipação Induzida por Opioides, Oxicodona, Humanos, Analgésicos Opioides/efeitos adversos, Peso Corporal, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/prevenção & controle, Laxantes/uso terapêutico, Constipação Induzida por Opioides/tratamento farmacológico, Oxicodona/efeitos adversos, Estudos RetrospectivosRESUMO
Complement component 3 (C3) deficiency has recently been known as a cause of constipation, without studies on the therapeutic efficacy. To evaluate the therapeutic agents against C3-deficiency-induced constipation, improvements in the constipation-related parameters and the associated molecular mechanisms were examined in FVB/N-C3em1Hlee/Korl knockout (C3 KO) mice treated with uridine (Urd) and the aqueous extract of Liriope platyphylla L. (AEtLP) with laxative activity. The stool parameters and gastrointestinal (GI) transit were increased in Urd- and AEtLP-treated C3 KO mice compared with the vehicle (Veh)-treated C3 KO mice. Urd and AEtLP treatment improved the histological structure, junctional complexes of the intestinal epithelial barrier (IEB), mucin secretion ability, and water retention capacity. Also, an improvement in the composition of neuronal cells, the regulation of excitatory function mediated via the 5-hydroxytryptamine (5-HT) receptors and muscarinic acetylcholine receptors (mAChRs), and the regulation of the inhibitory function mediated via the neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) were detected in the enteric nervous system (ENS) of Urd- and AEtLP-treated C3 KO mice. Therefore, the results of the present study suggest that C3-deficiency-induced constipation can improve with treatment with Urd and AEtLP via the regulation of the mucin secretion ability, water retention capacity, and ENS function.
Assuntos
Complemento C3, Extratos Vegetais, Camundongos, Animais, Camundongos Knockout, Uridina/farmacologia, Uridina/uso terapêutico, Extratos Vegetais/farmacologia, Extratos Vegetais/uso terapêutico, Extratos Vegetais/química, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/induzido quimicamente, Mucinas, ÁguaRESUMO
BACKGROUND: Perturbations of animal-associated microbiomes from chemical stress can affect host physiology and health. While dysbiosis induced by antibiotic treatments and disease is well known, chemical, nonantibiotic drugs have recently been shown to induce changes in microbiome composition, warranting further exploration. Loperamide is an opioid-receptor agonist widely prescribed for treating acute diarrhea in humans. Loperamide is also used as a tool to study the impact of bowel dysfunction in animal models by inducing constipation, but its effect on host-associated microbiota is poorly characterized. RESULTS: We used conventional and gnotobiotic larval zebrafish models to show that in addition to host-specific effects, loperamide also has anti-bacterial activities that directly induce changes in microbiota diversity. This dysbiosis is due to changes in bacterial colonization, since gnotobiotic zebrafish mono-colonized with bacterial strains sensitive to loperamide are colonized up to 100-fold lower when treated with loperamide. Consistently, the bacterial diversity of gnotobiotic zebrafish colonized by a mix of 5 representative bacterial strains is affected by loperamide treatment. CONCLUSION: Our results demonstrate that loperamide, in addition to host effects, also induces dysbiosis in a vertebrate model, highlighting that established treatments can have underlooked secondary effects on microbiota structure and function. This study further provides insights for future studies exploring how common medications directly induce changes in host-associated microbiota. Video Abstract.
Assuntos
Loperamida, Microbiota, Humanos, Animais, Loperamida/efeitos adversos, Peixe-Zebra/microbiologia, Disbiose/induzido quimicamente, Constipação Intestinal/induzido quimicamente, BactériasRESUMO
OBJECTIVE: To investigate whether Hetong decoction (, HTT) alleviates constipation via regulating AQPs expression. METHODS: Constipation in rats was induced by loperamide, and rats were randomly assigned into model (saline), HHT-low (95 g/kg), HTT-medium (190 g/kg), HTT-high (380 g/kg) and positive control (mosapride) groups. Then the defecation function, the concentration of serum arginine vasopressin (AVP) and cyclic adenosine monophosphate (cAMP), and the expression of AQP3 and AQP8 in colon tissues were assessed. NCM460 colon cells with AQP3 and AQP8 knockdown or overexpression were exposed to serum from rats that received low or high dose of HTT, followed by detection of AQP3 and AQP8 expression. RESULTS: The model group showed lower fecal weight and water content, weaker intestinal transit, higher serum concentration of AVP and cAMP, increased proximal and distal AQP8 expression, increased proximal but decreased distal AQP3 expression. However, these trends were reversed in both the HTT group (low, medium and high dose) and the positive control group. In NCM460 cells, HTT dose-dependently stabilized AQP3 and AQP8 expression under AQP3/8 plasmid interference or overexpression. CONCLUSIONS: HTT relieves constipation in rats through regulating AQP3 and AQP8 expression.
Assuntos
Aquaporinas, Loperamida, Ratos, Animais, Loperamida/efeitos adversos, Loperamida/metabolismo, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Constipação Intestinal/genética, Aquaporinas/genética, Aquaporinas/metabolismo, Colo/metabolismo, Intestinos, AMP Cíclico/genética, AMP Cíclico/metabolismoRESUMO
PURPOSE: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve OIC control in cancer patients. METHODS: Following collaborative and prioritization techniques, a scientific committee generated statements addressing possible barriers to optimal OIC management (related to patients, health providers and health care system), and potential interventions to overcome these barriers. An expert panel of 36 oncologists assessed the statements to reach a consensus. RESULTS: The survey consisted of 70 statements. Consensus was reached on 12/45 items related to barriers (26.6%) and on 19/25 items about corrective interventions (76%). The panel considered that patients are unaware of the existence of a specific OIC treatment, and their information sources are highly variable and unreliable. Regarding health providers, the panel considered that the oncologists prioritize symptoms such as diarrhea, pain, anxiety, or other treatment toxicities, over constipation. Work overload and bureaucratic requirements were the main barriers related to health care system. Regarding potential interventions, best-rated proposals included specific training programs development for primary care physicians and nurses, and multiplatform informative resources development for patients and caregivers, including precisely written instructions about OIC recognition and management. Oncologists assessed positively measures aiming to improve coordination between primary care physicians and oncologists, and nursing consultations implementation. The panel considered useful the OIC treatment algorithms simplification. CONCLUSIONS: The expert panel identified the main barriers to optimal OIC management and suggested some feasible approaches to overcome these barriers.
Assuntos
Neoplasias, Constipação Induzida por Opioides, Humanos, Constipação Induzida por Opioides/tratamento farmacológico, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/terapia, Constipação Intestinal/diagnóstico, Analgésicos Opioides/efeitos adversos, Neoplasias/complicações, Neoplasias/tratamento farmacológico, Inquéritos e QuestionáriosRESUMO
Structural changes in the gut microbiota are closely related to the development of functional constipation, and regulating the gut microbiota can improve constipation. Rifaximin is a poorly absorbed antibiotic beneficial for regulating gut microbiota, but few studies have reported its effects on constipation. The purpose of this study was to investigate the effect of rifaximin on loperamide-induced constipation in SD rats. The results showed that rifaximin improved constipation by increasing serum 5-HT, SP, and the mRNA expression of AQP3, AQP8, and reducing the mRNA expression of TLR2 and TLR4. In addition, rifaximin could regulate the gut microbiota of constipated rats, such as increasing the potentially beneficial bacteria Akkermansia muciniphila and Lactobacillus murinus, reducing the Bifidobacterium pseudolongum. According to metabolomics analysis, many serum metabolites, including bile acids and steroids, were changed in constipated rats and were recovered via rifaximin intervention. In conclusion, rifaximin might improve loperamide-induced constipation in rats by increasing serum excitatory neurotransmitters and neuropeptides, modulating water metabolism, and facilitating intestinal inflammation. Muti-Omics analysis results showed that rifaximin has beneficial regulatory effects on the gut microbiota and serum metabolites in constipated rats, which might play critical roles in alleviating constipation. This study suggests that rifaximin might be a potential strategy for treating constipation.
Assuntos
Microbioma Gastrointestinal, Loperamida, Ratos, Animais, Loperamida/efeitos adversos, Rifaximina/efeitos adversos, Ratos Sprague-Dawley, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, RNA MensageiroRESUMO
Slow transit constipation (STC) is a prevalent chronic colonic dysfunction disease that significantly impairs the quality of life for affected individuals. Yunpi Tongbian Fang (YPTBF), a traditional Chinese medicine compound, has demonstrated promising clinical efficacy; however, its underlying mechanism remains elusive. In order to assess the laxative properties of YPTBF, which encompasses the influence on gut microbiota, gut metabolites, gut neurotransmitters, and colon histology, an oral administration of YPTBF was conducted for a duration of two consecutive weeks on STC rats induced by loperamide hydrochloride. The results showed that YPTBF improved the symptoms of STC, alleviated the decrease in total fecal volume and fecal water content caused by loperamide-induced constipation, restored intestinal transport function, and HE staining showed the recovery of pathological damage to the colon mucosa. In addition, YPTBF increased the concentrations of 5-HT and ACHE, while reducing the concentrations of VIP and NO. YPTBF adjusted the diversity and abundance of gut microbiota in STC rats, enabling the recovery of beneficial bacteria and promoting the production of acetic acid, propionic acid, and butyric acid. We found that YPTBF can improve constipation in STC rats, possibly by regulating the intestinal microbiota structure and improving SCFAs metabolism.
Assuntos
Microbioma Gastrointestinal, Loperamida, Ratos, Animais, Loperamida/efeitos adversos, Qualidade de Vida, Constipação Intestinal/induzido quimicamente, Constipação Intestinal/tratamento farmacológico, Ácidos Graxos Voláteis/efeitos adversos, Ácido ButíricoRESUMO
OBJECTIVE: High rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the effects of the BA transporter inhibitor elobixibat in patients with CC aged ≥60 years. DESIGN: We prospectively compared the RSTs of 17 patients with CC aged ≥60 years with those of 9 healthy individuals of the same age range. We next performed a prospective, randomised, parallel-group, double-blind, placebo-controlled clinical trial of 17 patients with CC who administered elobixibat or placebo daily for 1 week. Using barostat methodology, their first constant sensation volume (FCSV), defaecatory desire volume (DDV), and maximum tolerable volume (MTV) thresholds; their rectal compliance; and their faecal BA concentrations were measured before and after treatment. RESULTS: There were no significant differences in the RSTs of healthy individuals and patients with CC, but all of these tended to be higher in the latter group. Elobixibat increased the desire to defaecate, significantly reduced the threshold for FCSV (p=0.0018), and tended to reduce the threshold for DDV (p=0.0899) versus placebo. However, there were no differences in the MTV or rectal compliance of the two groups. The total faecal BA concentration increased, and particularly that of secondary BAs in the elobixibat group. Elobixibat was most efficacious in participants with a longer duration of CC and a history of treatment for CC. CONCLUSION: Elobixibat reduces the RSTs of patients with CC aged ≥60 years, which may be important for its therapeutic effects. TRIAL REGISTRATION NUMBER: jRCTs061200030.
