RESUMO
Gastroesophageal reflux disease (GERD) is associated with an incompetent lower esophageal sphincter (LES), resulting in the reflux of gastric contents into the esophagus. U46619, a thromboxane A2 (TXA2) receptor agonist, induces contractions in various smooth muscles. Therefore, this study aimed to investigate the effects and mechanisms of action of U46619 on the porcine LES. To achieve this, contractions of the clasp and sling strips of the porcine LES, induced by U46619, were measured using isometric transducers. Furthermore, the contractile mechanism of U46619 in the porcine LES was investigated by pretreating the strips with atropine (a muscarinic receptor antagonist), tetrodotoxin (a neuronal sodium channel blocker), nifedipine (a calcium channel blocker), and Ca2+-free Krebs-Henseleit solution. Additionally, reverse transcription polymerase chain reaction (PCR) and immunohistochemistry (IHC) were performed to determine the presence of the TXA2 receptor in porcine LES. The results of this study demonstrated that U46619 caused marked concentration-dependent contractions in both porcine sling and clasp strips. The mechanism of U46619-induced contraction of the porcine LES was found to be related to calcium channels. Furthermore, the reverse transcription PCR analysis and IHC revealed that the TXA2 receptor was expressed in the clasp and sling fibers of porcine LES. Consequently, this study suggests that U46619 mediates the contraction of porcine LES through calcium channels and has potential as a therapeutic approach for treating GERD. SIGNIFICANCE STATEMENT: This study establishes that U46619 induces concentration-dependent contractions in porcine LES, primarily mediated by calcium channels. The presence of the TXA2 receptor in LES clasp and sling fibers is confirmed. These findings highlight U46619's potential as a GERD therapeutic by targeting calcium channels for LES contraction modulation.
Assuntos
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Esfíncter Esofágico Inferior , Contração Muscular , Animais , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Contração Muscular/efeitos dos fármacos , Suínos , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiologia , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Masculino , FemininoRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) is associated with lower esophageal sphincter (LES) incompetence. In some patients, GERD is refractory to acid reduction therapy which is the main treatment for GERD. So far, medications that can increase LES tone are few. Arecae pericarpium (A. pericarpium) is a medication in Traditional Chinese Medicine known to promote intestinal motility. METHODS: We investigated the effect of A. pericarpium extracts on porcine LES motility. In addition, we used tetrodotoxin (TTX) and atropine to study the underlying mechanism of A. pericarpium extracts-induced contractions of LES. RESULTS: The results of this study showed that A. pericarpium extracts and their main active ingredient, arecoline, can induce the contractions of porcine LES sling and clasp muscles in a dose-response manner. TTX did not have an inhibitory effect on the contractions induced by A. pericarpium extracts and arecoline in LES. However, atropine significantly inhibited A. pericarpium extracts- and arecoline-induced contractions of LES. CONCLUSION: A. pericarpium extracts can induce the contractions of porcine LES in a dose dependent manner, possibly through muscarinic receptors, and hence, may be worth developing as an alternative therapy for GERD.
Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores Muscarínicos/metabolismo , Animais , Areca , Refluxo Gastroesofágico/tratamento farmacológico , Técnicas In Vitro , Suínos , TaiwanRESUMO
The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 µM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 µM carbenoxolone (a gap junction inhibitor), pretreatment with 100 µM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl--free solution. However, pretreatment with 100 µM Nω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 µM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.
Assuntos
Esfíncter Esofágico Inferior/fisiologia , Células Intersticiais de Cajal/metabolismo , Relaxamento Muscular/fisiologia , Receptores Nicotínicos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Anoctamina-1/metabolismo , Esfíncter Esofágico Inferior/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Células Intersticiais de Cajal/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Neurônios/metabolismo , Neurotransmissores/metabolismo , Agonistas Nicotínicos/farmacologia , SuínosRESUMO
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder. In the present study, we investigated TRP vanilloid subfamily member 2 (TRPV2) expression in lower oesophageal sphincter (LES) and its involvement in acid reflux oesophagitis in rats. Expression of TRPV2 and nerve growth factor mRNAs was significantly enhanced in LES of rats with reflux oesophagitis compared with normal rats. TRPV2 was mainly expressed in inhibitory motor neurons, and partly in intrinsic and extrinsic primary afferent neurons, and macrophages in LES of normal and reflux oesophagitis rats. Number of TRPV2-immunopositive nerve fibres was significantly increased, but that of nNOS-, CGRP-, and PGP9.5-nerve fibres was not changed in reflux oesophagitis compared with normal group. Probenecid produced nitric oxide production and relaxation in LES and this response was significantly enhanced in oesophagitis compared with normal group. Probenecid-induced relaxant effect was blocked by a TRPV2 inhibitor, tranilast, and a NOS inhibitor, NG-nitro-l-arginine methyl ester, in reflux oesophagitis rats. Oral administration of tranilast significantly improved body weight loss, oesophageal lesions, and epithelial thickness in oesophagitis model. These results suggest that up-regulation of TRPV2 in inhibitory motor neurons is involved in LES relaxation in oesophagitis model. TRPV2 inhibition might be beneficial for treatment of GERD.
Assuntos
Esfíncter Esofágico Inferior/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/genética , Expressão Gênica/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Animais , Modelos Animais de Doenças , Esfíncter Esofágico Inferior/efeitos dos fármacos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Probenecid/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/uso terapêuticoRESUMO
BACKGROUND: Administration of a bitter compound can alter the intragastric pressure (IGP) after a meal. Additionally, a negative correlation between IGP and the number of transient lower esophageal sphincter relaxations (TLESRs) has been demonstrated. However, the effect of a bitter tastant on the number of TLESRs and subsequent reflux episodes has never been investigated and it is unclear whether bitter food items should be avoided in gastro-esophageal reflux disease. We hypothesize that bitter administration in healthy volunteers (HVs) will lead to an increase in the number of TLESRs. METHODS: After an overnight fast, 20 female HVs (36 years [21-63]) underwent a high-resolution impedance manometry (HRiM) measurement. After placement of the HRiM probe, 0.1 ml/kg of a 10 mM denatonium benzoate solution (bitter) or an identical volume of water (placebo) was administered directly into the stomach. The number of TLESRs and reflux episodes was quantified 30 min before and 2 h after consumption of a high caloric meal. KEY RESULTS: There was no significant difference in the number of TLESRs or reflux episodes between the bitter and placebo condition. Additionally, no differences were observed in the nature (gas or liquid) and extent of reflux events. Lower esophageal sphincter pressures dropped significantly in the first postprandial hour to start recovering slowly back to baseline values during the second postprandial hour (p < 0.0001), without any difference between both conditions. CONCLUSIONS & INTERFERENCES: Administration of the bitter tastant denatonium benzoate has no influence on the number of TLESRs or reflux episodes.
Assuntos
Agentes Aversivos/farmacologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Paladar/fisiologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Refluxo Gastroesofágico , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Peristaltismo/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects. METHODS: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout. RESULTS: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo. CONCLUSIONS: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs.
Assuntos
Benzoatos/administração & dosagem , Esfíncter Esofágico Inferior/efeitos dos fármacos , Refluxo Gastroesofágico/prevenção & controle , Indenos/administração & dosagem , Relaxamento Muscular/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Tiazóis/administração & dosagem , Adulto , Estudos Cross-Over , Método Duplo-Cego , Endoscopia do Sistema Digestório/métodos , Esfíncter Esofágico Inferior/diagnóstico por imagem , Esfíncter Esofágico Inferior/fisiopatologia , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Manometria/métodos , Relaxamento Muscular/fisiologia , Período Pós-Prandial , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Endoscopic intrasphincteric injection of Botox (ISIB) is used routinely for the treatment of achalasia esophagus and other spastic motor disorders. Studies show that the ISIB reduces the smooth muscle lower esophageal sphincter (LES) pressure. The esophageal hiatus, formed by the right crus of diaphragm, surrounds the cranial half of the LES and works like an external LES. We studied the effects of ISIB on the LES and hiatal contraction and gastroesophageal reflux (GER). Fourteen patients treated with ISIB were studied. Esophageal manometry-impedance recordings were performed before and after the ISIB. Hiatal contraction was assessed during tidal inspiration, forced inspiration, Müller's maneuver, and straight leg raise. In 6 subjects, the manometry were repeated 6-12 mo after the ISIB. The esophagogastric junction (EGJ) pressure was measured at end expiration (LES pressure) and at the peak of maneuvers (hiatal contraction). Transdiaphragmatic pressure (pdi; force of diaphragmatic contraction) was measured at the peak of forced inspiration. GER was measured from the impedance recordings. The EGJ pressure at end expiration (LES pressure) decreased significantly after the Botox injection. The peak EGJ pressure at tidal inspiration, forced inspiration, Müller's maneuver, and straight leg raise was also dramatically reduced by the ISIB. There was no effect of Botox on the pdi during forced inspiration. Seven of 10 subjects demonstrated GER during maneuvers following the ISIB. Six to 12 mo after ISIB, the LES and hiatal contraction pressure returned to the pre-ISIB levels. ISIB, in addition to decreasing LES pressure, paralyzes the esophageal hiatus (crural diaphragm) and induces GER.NEW & NOTEWORTHY The sphincter mechanism at the lower end of the esophagus comprises smooth muscle lower esophageal sphincter (LES) and skeletal muscle crural diaphragm (hiatus). Current thinking is that the endoscopic intrasphincteric injection of Botox (ISIB), used routinely for the treatment of achalasia esophagus, reduces LES pressure. Our study shows that ISIB, even though injected into the LES, diffuses into the hiatus and causes its paralysis. These findings emphasize the importance of esophageal hiatus as an important component of the antireflux barrier and that the ISIB is refluxogenic.
Assuntos
Inibidores da Liberação da Acetilcolina/efeitos adversos , Toxinas Botulínicas Tipo A/efeitos adversos , Diafragma/efeitos dos fármacos , Acalasia Esofágica/tratamento farmacológico , Esfíncter Esofágico Inferior/efeitos dos fármacos , Refluxo Gastroesofágico/induzido quimicamente , Contração Muscular/efeitos dos fármacos , Paralisia Respiratória/induzido quimicamente , Inibidores da Liberação da Acetilcolina/administração & dosagem , Adulto , Idoso , Toxinas Botulínicas Tipo A/administração & dosagem , Diafragma/fisiopatologia , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/fisiopatologia , Esfíncter Esofágico Inferior/fisiopatologia , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Pressão , Paralisia Respiratória/diagnóstico , Paralisia Respiratória/fisiopatologia , Fatores de RiscoRESUMO
Background: Treatment options for achalasia include endoscopic and surgical techniques that carry the risk of esophageal bleeding and perforation. The rare coexistence of esophageal varices has only been anecdotally described and treatment is presumed to carry additional risk. Methods: Experience from physicians/surgeons treating this rare combination of disorders was sought through the International Manometry Working Group. Results: Fourteen patients with achalasia and varices from seven international centers were collected (mean age 61 ± 9 years). Five patients were treated with botulinum toxin injections (BTI), four had dilation, three received peroral endoscopic myotomy (POEM), one had POEM then dilation, and one patient underwent BTI followed by Heller's myotomy. Variceal eradication preceded achalasia treatment in three patients. All patients experienced a significant symptomatic improvement (median Eckardt score 7 vs 1; p < 0.0001) at 6 months follow-up, with treatment outcomes resembling those of 20 non-cirrhotic achalasia patients who underwent similar therapy. No patients had recorded complications of bleeding or perforation. Conclusion: This study shows an excellent short-term symptomatic response in patients with esophageal achalasia and varices and demonstrates that the therapeutic outcomes and complications, other than transient encephalopathy in both patients who had a portosystemic shunt, did not differ to disease-matched patients without varices.
Assuntos
Acalasia Esofágica/terapia , Varizes Esofágicas e Gástricas/terapia , Idoso , Toxinas Botulínicas/administração & dosagem , Dilatação/estatística & dados numéricos , Acalasia Esofágica/complicações , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/cirurgia , Varizes Esofágicas e Gástricas/complicações , Esofagoscopia/métodos , Feminino , Seguimentos , Miotomia de Heller/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Esophagogastric junction outflow obstruction (EGJOO) is a major motility disorder based on the Chicago Classification of esophageal motility disorders. This entity involves a heterogenous group of underlying etiologies. The diagnosis is reached by performing high-resolution manometry. This reveals evidence of obstruction at the esophagogastric junction, manifested by an elevated integrated relaxation pressure (IRP) above a cutoff value (IRP threshold varies by the manometric technology and catheter used), with preserved peristalsis. Further tests like endoscopy, timed barium esophagram, and cross-sectional imaging can help further elucidate the underlying etiology and rule out mechanical causes. Treatment is tailored to the underlying cause. Similar to achalasia, treatment targeting lower esophageal sphincter disruption like pneumatic dilation, peroral endoscopic myotomy, and botulinum injection are used in patients with functional EGJOO and persistent symptoms.
Assuntos
Transtornos da Motilidade Esofágica/diagnóstico , Esfíncter Esofágico Inferior/patologia , Esofagoscopia/métodos , Manometria/métodos , Antitoxina Botulínica/administração & dosagem , Dilatação/métodos , Transtornos da Motilidade Esofágica/patologia , Transtornos da Motilidade Esofágica/terapia , Esfíncter Esofágico Inferior/diagnóstico por imagem , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/cirurgia , Miotomia/métodos , Resultado do TratamentoRESUMO
Cholecystokinin (CCK) is known to cause lower esophageal sphincter (LES) relaxation through the activation of inhibitory motor neurons. CCK receptor agonists increase the frequency of transient LES relaxation through a peripheral mechanism. Recent studies show that the longitudinal muscle contraction (LMC)-related axial stretch might play a role in the LES relaxation by activating the mechanosensitive inhibitory motor neurons. The aim of our study was to determine whether the CCK-induced LES relaxation and the characteristics of LMC resemble those seen with spontaneous transient LES relaxation in humans. Nine healthy volunteers (5 Fr, 40 ± 12 yr) received escalating doses of CCK-octapeptide (CCK-8) (5, 10, 20, and 40 ng/kg). All subjects demonstrated a monophasic response to 5 ng/kg of CCK-8. In the majority of subjects, this response consisted of partial LES relaxation. All subjects showed a biphasic response to 40 ng/kg of CCK-8. The latter in most subjects consisted of 1) a period of partial relaxation followed by 2) complete LES relaxation along with crural diaphragm inhibition. The length of the esophagus decreased by 0.9 ± 0.4 cm, and muscle thickness increased by 40 ± 14% to 1.4 ± 0.2 mm ( P < 0.05) during initial partial LES relaxation. During complete LES relaxation there was greater LMC, as demonstrated by an esophageal shortening of 1.9 ± 0.5 cm and an increase in muscle thickness of 100 ± 16% ( P < 0.01). The complete phase 2 LES relaxation typically terminated with a robust after-contraction. Atropine significantly attenuated the CCK-induced esophageal LMC, prevented crural diaphragm inhibition, and abolished the phase 2 complete LES relaxation. NEW & NOTEWORTHY The phenotypic features of CCK-induced longitudinal muscle contraction (LMC), complete lower esophageal sphincter (LES) relaxation, and crural diaphragm inhibition, followed by a robust after-contraction, resemble those seen during spontaneous transient LES relaxation. A strong temporal relationship between the LMC and complete transient LES relaxation supports our hypothesis that the LMC plays an important role in the LES relaxation and crural diaphragmatic inhibition.
Assuntos
Colecistocinina/farmacologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Fármacos Gastrointestinais/farmacologia , Relaxamento Muscular , Fragmentos de Peptídeos/farmacologia , Adulto , Esfíncter Esofágico Inferior/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Most pregnant women have symptoms of gastroesophageal reflux disease (GERD) during pregnancy. Postmenopausal hormone replacement therapy is associated with GERD. The effects of estradiol on lower esophageal sphincter (LES) motility and GERD are not clearly known. The purpose of this study is to investigate the effects of estradiol on the motility of the porcine LES. Relaxations of clasp and sling strips of porcine LES caused by estradiol were measured using isometric transducers. We investigated the mechanism of estradiol-induced relaxation of the porcine LES using tetraethylammonium, apamine, iberiotoxin, glibenclamide, KT5720, KT5823, NG-nitro-l-arginine, tetrodotoxin, and ω-conotoxin GVIA. Reverse transcription polymerase chain reaction (PCR) analysis and immunohistochemistry (IHC) were performed to determine the existence of the G protein-coupled estrogen receptor (GPER) in the porcine LES. In endothelin-1-precontracted porcine LES strips, estradiol caused marked relaxations in a concentration-dependent manner. The mechanism of estradiol-induced relaxation on the porcine LES was associated with the potassium channel. Reverse transcription PCR analysis and IHC revealed that GPER was expressed in the sling and clasp fibers of the porcine LES. This finding suggests that GPER mediates the relaxation of the porcine LES. Estradiol may play a role in LES motility.
Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiologia , Estradiol/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Esfíncter Esofágico Inferior/metabolismo , Óxido Nítrico/metabolismo , Canais de Potássio/metabolismo , Rolipram/farmacologia , Suínos , Dicloridrato de Vardenafila/farmacologiaRESUMO
We compared dilator actions of representative four Ca2+ channel blockers on the isolated lower esophagus sphincter (LES) and thoracic aorta from rats. Verapamil, diltiazem, nifedipine and cilnidipine suppressed KCl-induced contractions of LES and thoracic aorta in a concentration-dependent manner. The order of selectivity for LES, which was calculated as ratio of IC50 value for thoracic aorta divided by that for LES, was diltiazem > verapamil > nifedipine > cilnidipine. These results suggest that diltiazem more preferentially dilates the LES whereas cilnidipine is expected to have lower potential risk of gastroesophageal dysfunction during the antihypertensive therapy.
Assuntos
Aorta/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Diltiazem/farmacologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Nifedipino/farmacologia , Verapamil/farmacologia , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Di-Hidropiridinas/efeitos adversos , Diltiazem/efeitos adversos , Relação Dose-Resposta a Droga , Refluxo Gastroesofágico/induzido quimicamente , Técnicas In Vitro , Masculino , Nifedipino/efeitos adversos , Cloreto de Potássio/farmacologia , Ratos Wistar , Verapamil/efeitos adversosRESUMO
Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, ß2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from ß2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from ß2 agonists. This increased cancer risk in ß2 agonist users merits further investigation.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Benzodiazepinas/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Neoplasias Esofágicas/epidemiologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Nitratos/efeitos adversos , Xantinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Factuais , Inglaterra/epidemiologia , Neoplasias Esofágicas/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Escócia/epidemiologia , Autorrelato , Adulto JovemRESUMO
The management of proton pump inhibitor-refractory GERD (rGERD) is a challenge in clinical practice. Since up to one-third of patients with typical GERD symptoms (heartburn and/or acid regurgitation) are not satisfied with proton pump inhibitor (PPI) therapy, new drug development targeting different pathophysiologies of GERD is imperative. At present, no other drugs serve as a more potent acid suppression agent than PPIs. As an add-on therapy, histamine type-2 receptor antagonists, alginates, prokinetics and transient lower esophageal sphincter relaxation inhibitors have some impact on the subgroups of rGERD, but greater effectiveness and fewer adverse effects for widespread use are required. Visceral hypersensitivity also contributes to the perception of GERD symptoms, and neuromodulators including antidepressants play a role in this category. Esophageal pH-impedance monitoring helps to distinguish functional heartburn from true GERD, and psychologic medication and cognitive behavior therapy are further therapy options instead of PPIs.
Assuntos
Alginatos/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Esfíncter Esofágico Inferior/efeitos dos fármacos , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Ácido Glucurônico/uso terapêutico , Ácidos Hexurônicos/uso terapêutico , HumanosRESUMO
Up to 40% of patients report persistent gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for medical therapy for PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 40 unique articles specific to the impact of PPI metabolizer genotype on PPI response and the use adjunctive medical therapies were identified. Thirteen articles reported impacts on CYP genotypes on PPI metabolism demonstrating lower endoscopic healing rates in extensive metabolizers; however, outcomes across genotypes were more uniform with more CYP independent PPIs rabeprazole and esomeprazole. Twenty-seven publications on 11 adjunctive medications showed mixed results for adjunctive therapies including nocturnal histamine-2 receptor antagonists, promotility agents, transient lower esophageal sphincter relaxation inhibitors, and mucosal protective agents. Utilizing PPI metabolizer genotype or switching to a CYP2C19 independent PPI is a simple and conservative measure that may be useful in the setting of incomplete acid suppression. The use of adjunctive medications can be considered particularly when the physiologic mechanism for PPI nonresponse is suspected. Future studies using adjunctive medications with improved study design and patient enrollment are needed to better delineate medical management options before proceeding to antireflux interventions.
Assuntos
Citocromo P-450 CYP2C19/genética , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/genética , Inibidores da Bomba de Prótons/uso terapêutico , Baclofeno/uso terapêutico , Benzamidas/uso terapêutico , Esfíncter Esofágico Inferior/efeitos dos fármacos , Fármacos Gastrointestinais/uso terapêutico , Genótipo , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Morfolinas/uso terapêutico , Relaxantes Musculares Centrais/uso terapêutico , Relaxamento Muscular/efeitos dos fármacos , Falha de TratamentoRESUMO
The sphincters failure is a part of NSAIDs-toxicity that can be accordingly counteracted. We used a safe stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, external and internal fistulas in rats, and particularly counteracts all NSAIDs-lesions. We assessed lower esophageal sphincter and pyloric sphincter pressure (cmH2O) in rats treated with various NSAIDs regimens, at corresponding time points, known to produce stomach, small intestine lesions, hepatotoxicity and encephalopathy. Assessment was after diclofenac (12.5 mg/kg, 40 mg/kg intraperitoneal challenge), ibuprofen (400 mg/day/kg intraperitoneally for 4 weeks), paracetamol (5.0 g/kg intraperitoneal challenge), aspirin (400 mg/kg intraperitoneally or intragastrically), celecoxib (0.5 mg/kg, 1.0 mg/kg intraperitoneally). BPC 157 (10 µg/kg, 10 ng/kg) was given immediately after NSAIDs (intraperitoneally or intragastrically) or given in drinking water. Regularly, in all control NSAIDs fall of pressure occurred in both sphincters rapidly and then persisted. By contrast, in all NSAIDs-rats that received BPC 157, initial fall of pressure was minimized and pressure values restored to normal values. All tested NSAIDs decrease pressure in both sphincters, whilst BPC 157 counteracts their effects and restored both sphincters function.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Antiulcerosos/farmacologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Piloro/efeitos dos fármacos , Acetaminofen/toxicidade , Animais , Aspirina/toxicidade , Celecoxib/toxicidade , Diclofenaco/toxicidade , Ibuprofeno/toxicidade , Masculino , Pressão , Ratos WistarRESUMO
BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.
Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Indóis/administração & dosagem , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Animais , Cães , Método Duplo-Cego , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiopatologia , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Endogenous opioids (EO) acting on µ-opiod receptors in central and enteric nervous system (ENS) control gastrointestinal motility but it is still unclear whether EO in ENS may control esophageal function in man, thus we will study the effects of methylnaltrexone (MNTX), a peripherally selective, and naloxone (NA), a non-selective µ-opiod receptor antagonist, on esophageal motility in healthy subjects. METHODS: Fifteen HV (6 M; 34.1 ± 0.6 years; BMI: 22.1 ± 0.1 kg/m2 ) underwent three esophageal high-resolution manometry impedance (HRiM) studies with 10 saline swallows administered every 30 minutes: drug was administered after 30 minutes (MNTX subcutaneously/NA or saline intravenously), a solid meal after 90 minutes; measurements continued for 120 minutes postprandially. KEY RESULTS: Methylnaltrexone did not significantly decrease the upper esophageal sphincter (UES) percentage of relaxation preprandially (72.5 ± 5 vs 66.9 ± 4.6 and 73 ± 3.8%, ANOVA between placebo, MNTX and NA, P=NS) and postprandially (60 minutes: 68.2 ± 5.6 vs 61 ± 5.5 and 67.1 ± 5.6%; 120 minutes: 68 ± 5.9 vs 59.3 ± 5.2 and 67.7 ± 4.7%; ANOVA between placebo, MNTX and NA, P=NS). MNTX and NA did not significantly alter preprandial and postprandial LES resting pressures and integrated relaxation pressure (ANOVA between placebo, MNTX and NA, all P=NS). Peak front velocity and distal contractile integral were not altered pre- and postprandially by MNTX and NA (ANOVA between placebo, MNTX and NA, P=NS). Transient lower esophageal sphincter relaxations (TLESRs') number was not altered by MNTX and NA (ANOVA between placebo, MNTX and NA, all P=NS). CONCLUSIONS AND INFERENCES: The peripheral selective and non-selective µ-opioid receptor antagonists MNTX and NA, respectively, do not alter TLESRs occurrence and esophageal peristalsis.
Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Adolescente , Adulto , Estudos Cross-Over , Monitoramento do pH Esofágico/métodos , Feminino , Humanos , Masculino , Naltrexona/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/fisiologia , Método Simples-Cego , Adulto JovemAssuntos
Analgésicos Opioides/efeitos adversos , Buprenorfina/efeitos adversos , Espasmo Esofágico Difuso/induzido quimicamente , Esfíncter Esofágico Inferior/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Buprenorfina/administração & dosagem , Buprenorfina/uso terapêutico , Transtornos de Deglutição/etiologia , Feminino , Humanos , Dor Lombar/tratamento farmacológico , Manometria , Pessoa de Meia-Idade , Adesivo TransdérmicoRESUMO
AIM: To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS: Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 µg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 µg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS: BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats). CONCLUSION: Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.