Investigation the relaxant effects of proton pump inhibitors and their relaxation mechanism on sheep sphincter of Oddi.

BACKGROUND: Using a relaxant agent before an endoscopic retrograde cholangiopancreatography (ERCP) might reduce complications. STUDY AIMS: We aimed to investigate the relaxant effects of proton pump inhibitors (PPIs) on sheep sphincter of Oddi (SO) and the mechanisms that might take part in this relaxant effect. PATIENTS AND METHODS: The sheep SO was mounted in an organ bath filled with Krebs-Ringer bicarbonate solution under 1.5 g tension and the relaxant effects of PPIs were evaluated in the tissues precontracted by carbachol (10-6 mol/l). The relaxant responses to the PPIs were tested in the presence of various blockers to enlighten the underlying mechanism by the PPIs. RESULTS: The PPIs exerted relaxant responses in a concentration-dependent manner in the sheep SO (P < 0.05). Esomeprazole produced the strongest relaxation. The administration of atropine, indomethacin, L-NAME, methylene blue, clotrimazole, glibenclamide, and 4-aminopyridine into the organ baths did not change the relaxations induced by PPIs in vitro (P> 0.05). On the other hand, Ca+2-activated potassium channel blocker tetraethylammonium (TEA) reduced the relaxation responses created by PPIs (P < 0.05). CONCLUSIONS: The present study suggests that PPIs create relaxation on SO partially via Ca+2-activated potassium channels. PPIs, especially esomeprazole, may be beneficial during the ERCP procedure. Further clinical studies are needed to confirm our results.

Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and treatment.

BACKGROUND: Post endoscopic retrograde cholangiopancreatography (ERCP) is comparatively complex application. Researchers has been investigated prevention of post-ERCP pancreatitis (PEP), since it has been considered to be the most common complication of ERCP. Although ERCP can lead various complications, it can also be avoided.AIMSTo study the published evidence and systematically review the literature on the prevention and treatment for PEP. METHODS: A systematic literature review on the prevention of PEP was conducted using the electronic databases of ISI Web of Science, PubMed and Cochrane Library for relevant articles. The electronic search for the review was performed by using the search terms "Post endoscopic retrograde cholangiopancreatography pancreatitis" AND "prevention" through different criteria. The search was restricted to randomized controlled trials (RCTs) performed between January 2009 and February 2019. Duplicate studies were detected by using EndNote and deleted by the author. PRISMA checklist and flow diagram were adopted for evaluation and reporting. The reference lists of the selected papers were also scanned to find other relevant studies. RESULTS: 726 studies meeting the search criteria and 4 relevant articles found in the edited books about ERCP were identified. Duplicates and irrelevant studies were excluded by screening titles and abstracts and assessing full texts. 54 studies were evaluated for full text review. Prevention methods were categorized into three groups as (1) assessment of patient related factors; (2) pharmacoprevention; and (3) procedural techniques for prevention. Most of studies in the literature showed that young age, female gender, absence of chronic pancreatitis, suspected Sphincter of Oddi dysfunction, recurrent pancreatitis and history of previous PEP played a crucial role in posing high risks for PEP. 37 studies designed to assess the impact of 24 different pharmacologic agents to reduce the development of PEP delivered through various administration methods were reviewed. Nonsteroidal anti-inflammatory drugs are widely used to reduce risks for PEP. Rectal administration of indomethacin immediately prior to or after ERCP in all patients is recommended by European Society for Gastrointestinal Endoscopy guidelines to prevent the development of PEP. The majority of the studies reviewed revealed that rectally administered indomethacin had efficacy to prevent PEP. Results of the other studies on the other pharmacological interventions had both controversial and promising results. Thirteen studies conducted to evaluate the efficacy of 4 distinct procedural techniques to prevent the development of PEP were reviewed. Pancreatic Stent Placement has been frequently used in this sense and has potent and promising benefits in the prevention of PEP. Studies on the other procedural techniques have had inconsistent results. CONCLUSION: Prevention of PEP involves multifactorial aspects, including assessment of patients with high risk factors for alternative therapeutic and diagnostic techniques, administration of pharmacological agents and procedural techniques with highly precise results in the literature.

[Morphine induced biliary pain. Case report]. / Cólico biliar inducido por morfina.

Morphine produces contraction of Oddi’s sphincter, which can be severe and of longer duration in some pathological conditions. This exaggerated response can manifest as a colicky biliary pain, frequently accompanied by a dramatic increase in hepatic enzymes. We report a 32 years old female who consulted in the emergency room for severe low abdominal pain of gynecologic origin, which was completely controlled by morphine. However, she presented a sudden epigastric colicky pain irradiating in the back, which persisted for several hours in spite of the repeated administration of analgesics. Transaminases elevated from previously normal value to over 1,000 U/L, and returned to the normal level without further treatment after several days. Magnetic resonance cholangiography showed normal fine bile duct, without stones. This transient increase in hepatic enzymes was considered as a consequence of high biliary pressure secondary to morphine-induced spastic contraction of Oddi’s sphincter and a consecutive hepatocellular necrosis.

Cólico biliar inducido por morfina / Morphine induced biliary pain: case report

Morphine produces contraction of Oddi’s sphincter, which can be severe and of longer duration in some pathological conditions. This exaggerated response can manifest as a colicky biliary pain, frequently accompanied by a dramatic increase in hepatic enzymes. We report a 32 years old female who consulted in the emergency room for severe low abdominal pain of gynecologic origin, which was completely controlled by morphine. However, she presented a sudden epigastric colicky pain irradiating in the back, which persisted for several hours in spite of the repeated administration of analgesics. Transaminases elevated from previously normal value to over 1,000 U/L, and returned to the normal level without further treatment after several days. Magnetic resonance cholangiography showed normal fine bile duct, without stones. This transient increase in hepatic enzymes was considered as a consequence of high biliary pressure secondary to morphine-induced spastic contraction of Oddi’s sphincter and a consecutive hepatocellular necrosis.

Expression and alteration of BKCa channels in the sphincter of Oddi's from rabbits with hypercholesterolemia.

This study aimed to investigate the expression and function of BKCa channels in the Sphincter of Oddi (SO) in a rabbit model of hypercholesterolemia (HC). New Zealand white rabbits were randomly divided into 2 groups: the control group was fed standard chow (n = 18) whereas the high-cholesterol group was fed cholesterol-enriched chow containing 1.5% cholesterol (n = 18). The serum cholesterol level was significantly greater in the HC groups than in the control group, but there was no significant difference in body weight between the control and HC groups. Although the total protein expression of BKCa α- and ß1-subunit was not significantly different between the control and HC groups, the Tyr-phosphorylation of BKCa α-subunit was significantly decreased in the HC group than in the control group. In addition, hypercholesterolemia significantly increased Acetylcholine (ACh)-induced contraction of the SO rings. Pretreatment with 30 µM NS1619, a BKCa channel agonist, significantly reduced ACh-induced contraction of the SO rings in HC rabbits. Moreover, pretreatment with 100 µM Na3OV4, a protein tyrosine phosphatase inhibitor, significantly reduced ACh-induced contraction of the SO rings in HC rabbits, whereas it significantly increased upon pretreating with 10 µM Genistein, a tyrosine kinase inhibitor. Whole-cell patch clamp recordings showed that BKCa current density was significantly lower in SOSMCs from HC group than that from control group. Our findings suggest that hypercholesterolemia-induced downregulation of BKCa channel, and Tyr-phosphorylation of BKCa α-subunit may contribute to the hyperresponsiveness of the SO ring in HC rabbits.

Periarticular Morphine-Induced Sphincter of Oddi Spasm Causing Severe Pain and Bradycardia in an Awake Patient Under Spinal Anesthesia: An Important Diagnostic Consideration.

Sphincter of Oddi spasm from opioids has been documented, presenting as severe epigastric pain and potentially overlooked in a differential diagnosis. We present a case of sphincter of Oddi spasm from periarticular morphine in a patient under spinal anesthesia, causing severe distress and treated effectively with glucagon. It is important for anesthesiologists using opioids to consider it as a cause of perioperative pain and be familiar with treatment as it may be refractory by conventional use of opioids for pain relief. It is also important to consider the systemic effects of periarticular absorption, as evident by our case.

Effects of remifentanil on the sphincter of Oddi in a 3-year-old child: a case report.

Opioids cause spasm of the sphincter of Oddi. Remifentanil is metabolized enzymatically throughout the body. Its context-sensitive half-time is 3 to 4minutes. The effect of remifentanil on the sphincter of Oddi is unknown, especially in children. We recently encountered a patient in whom the administration of remifentanil caused spasm of the sphincter of Oddi, which resolved rapidly after discontinuation of remifentanil. A 3-year-old girl weighing 11.3kg was scheduled to undergo common bile duct excision with ductoplasty. Her diagnosis was congenital biliary dilatation. In the operating room, after achieving the initial induction through sevoflurane (5%) and intravenous rocuronium (10mg), she was intubated and administered a continuous paravertebral block by levobupivacaine (25mg/10mL +2.5mg/h). General anesthesia was maintained with sevoflurane (2%), remifentanil (0.5 µg kg(-1) min(-1)), and oxygen (fractional inspired oxygen tension, 0.33). The first intraoperative cholangiogram obtained via the cystic duct tube showed obstruction at the terminal end of the common bile duct. We injected scopolamine butylbromide (5mg, intravenous) to relax the sphincter of Oddi. However, the next cholangiogram obtained 3minutes later still showed an obstruction. We speculated that the obstruction may have been caused by remifentanil-induced spasm of the sphincter of Oddi. Therefore, we stopped administering remifentanil; 2minutes later, we achieved satisfactory passage of the contrast material to the duodenum. The predicted plasma concentrations of remifentanil at the time of stopping its administration and at the time of disobliteration were 6.38and 2.55ng/mL, respectively. The patient's postoperative course was uneventful. In patients who have spasms of the sphincter of Oddi during the administration of remifentanil, the resultant obstruction can be treated effectively by reducing the infusion rate of remifentanil.

Influence of paeoniflorin on intracellular calcium ion concentration in the sphincter of Oddi of hypercholesterolemic rabbits.

This study aimed to investigate the influence of hypercholesterolemia (HC) on intracellular calcium ion concentration in the sphincter of Oddi (SO) of rabbits and the influence of paeoniflorin on intracellular calcium ion concentration in the hypercholesterolemic rabbit SO. Sixteen purebred New Zealand rabbits were randomly divided into two groups: the control group and the HC model group (8 rabbits in each group). The control group was fed standard diet. The HC group was fed standard diet plus cholesterol for a total of 8 weeks to induce and establish the rabbit HC model. The SO segment of HC rabbits was taken and enzyme treated to obtain SO cells. After primary culture, immunohistochemical analysis was performed. Fluo-3/AM was used to load SO cells, and then intracellular calcium ion concentration was determined by confocal microscopy. Intracellular calcium ion in the SO of the HC group was higher than that of the normal group; intracellular calcium ion in the HC rabbit SO of the paeoniflorin group was lower than that of the control group, where the paeoniflorin effect was greater with higher concentrations. High cholesterol caused an increase in intracellular calcium ion concentration in the rabbit SO, and paeoniflorin can reduce intracellular calcium ion concentration in the HC rabbit SO in a concentration-dependent manner.

Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder.

Opioid analgesics are widely believed to cause spasm of the bile duct sphincter and so impede bile flow. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence; however, to date, no studies have reported the effects of thienorphine on the function of the biliary tract. This study examined the in vivo effects of thienorphine on the guinea pig isolated sphincter of Oddi, choledochus and gall bladder and on bile flow. The area under the curve (AUC) of isolated sphincter of Oddi was not influenced by thienorphine or buprenorphine, whereas morphine increased the AUC of the isolated sphincter of Oddi in a concentration-dependent manner. Thienorphine and buprenorphine concentration-dependently decreased the AUC of isolated choledochus, while morphine increased the AUC of isolated choledochus. Thienorphine had no effect on the contractile amplitude or basal tension of isolated gall bladder muscle strips. In contrast, buprenorphine and morphine increased the contractile basal tension of isolated gall bladder muscle strips in a concentration-dependent manner. Thienorphine (0.01-1.0mg/kg) had no significant inhibitory effect on bile flow. However, morphine (1.0-10mg/kg) and buprenorphine (1.0mg/kg) significantly inhibited bile flow. The maximum inhibition of bile flow by buprenorphine was 63.9±12.9% and by morphine was 74.1±11.3%. In summary, thienorphine has little influence on the guinea pig isolated sphincter of Oddi, choledochus and gall bladder or on bile flow, which may result in a lack of adverse biliary colic effects.

Effects of cholecystectomy on the changes of motility of Beagle dogs' sphincter of Oddi.

PURPOSE: To observe the effect of cholecystectomy on the changes of motion pattern of Beagle dogs' sphincter of Oddi (SO), and investigate the modulatory role of nitric oxide (NO) and cholecystokinin (CCK) in the regulation of SO. METHODS: Pressure of common bile duct, SO motility, response to bolus injections of cholecystokinin (CCK, 20 ng/kg and 100 ng/kg), basal pressure (BP) and phasic contraction amplitude (PCA) were measured respectively by manometry in six Beagle dogs before and after cholecystectomy. RESULTS: After cholecystectomy, the pressure and diameter of common bile ducts (CBD) was significantly increased (p<0.01); BP and phasic contraction frequency (PCF) were also increased, however, no significant differences were found between the two groups; the SO motilities was not significantly changed. The relaxation responded to physiological dose of CCK (20ng/kg) was decreased, while bolus-dose of CCK (100ng/kg) induced rapid contractions and decreased PCA after cholecystectomy. The regulation pattern of SO pressure modulated by NO and its inhibitor had changed after cholecystectomy. CONCLUSION: After cholecystectomy in Beagle dogs, no obviously change of motion pattern of SO was observed through self-compensation, but these compensations may lead to some changes of regulation pattern of CCK and NO on SO.

Castanea sativa Mill. extract contracts gallbladder and relaxes sphincter of Oddi in guinea pig: a natural approach to biliary tract motility disorders.

Impaired gallbladder motility is a contributing factor to gallstone formation. Since many drugs delaying intestinal motility inhibit gallbladder emptying, the aim of the present study was to evaluate the effect on gallbladder and sphincter of Oddi motility of a Natural Chestnut Wood Extract (NEC) that reduces intestinal motility. In order to evaluate the effect of the extract in normal- and high-risk gallstone conditions, the investigation was performed using tissues from animals fed normal and lithogenic diet. Fifty guinea pigs were administered either control or lithogenic diet. The spontaneous motility of the gallbladder and sphincter of Oddi were recorded on isolated gallbladder tissues; thereafter, the effect of NEC on motility was tested and compared with carbachol (CCh), potassium chloride (KCl), noradrenaline (NA), and A71623. Compared to controls, the lithogenic diet induced an irregular and disordered motor pattern in both the gallbladder and sphincter of Oddi. NEC increased gallbladder and decreased sphincter of Oddi spontaneous motility independently of cholinergic, adrenergic, and CCK-1 receptor-mediated pathways both in controls and in lithogenic diet-fed animals, although the effect was lower in the latter group. The effect was reversible and mediated by calcium channels. The natural extract of chestnut increasing gallbladder contraction and inducing the relaxation of the sphincter of Oddi can be of benefit in pathological conditions associated with increased transit time at risk of gallstones.

[Effectiveness of treatment of pancreatic disorders in children (based on catamnesis)].

In the article results of supervision of the patients with chronic pancreatitis and dysfunction of Oddi's sphincter, pancreatic type, in polyclinic were presented. Among them: 50 children received in clinic therapeutic complex offered by us which included: phytoenzyme, spasmolytic and antioxidant. 50 children were treated in traditional way. Screening of functional condition of the pancreas revealed decreasing percentage of moderate exocrine insufficiency of pancreas (10% of incidences) in children with recurrent course of pancreatitis. In long-lasting course of pancreatitis in this group percentage of patients with moderate exocrine insufficiency was decreased due to 15%. At the same time, in patients with moderate and severe exocrine insufficiency (55 and 20% subsequently) which improves non complete efficiency of basic therapy.

Effects of cannabinoid agonists on sheep sphincter of oddi in vitro.

BACKGROUND/AIMS: According to recent studies, the endocannabinoid system plays an important role in both physiological and pathophysiological situations. The purpose of the present study was to investigate the effects of cannabinoid (CB) agonists on isolated sheep sphincter of Oddi (SO)in vitro. METHODS: The isolated sheep SO tissues were mounted in organ baths and tested for isometric tension and cyclic GMP levels (cGMP) in response to the non-selective CB receptor agonist WIN 55,212-2 and the potent CB1 receptor agonist methanandamide in the presence and absence of the selective CB1 antagonist SR 141716A, the selective CB2 antagonist SR 144528 and the nonspecific inhibitor of nitric oxide (NO) synthase L-NAME. RESULTS: CB agonists relaxed SO in a concentration-dependent manner. These relaxations did not reduce in the presence of SR 144528 but were significantly reduced by SR 141716A and L-NAME. Carbachol significantly increased the cGMP levels compared with the control group and both of the CB receptor agonists significantly increased the cGMP levels compared with the control and carbachol groups. On the other hand, L-NAME prevented the increase in cGMP levels caused by CB agonists. CONCLUSION: These results show that the relaxation by the agonists may be through CB1 receptors. The decrease of CB relaxation responses by L-NAME, a nonspecific inhibitor of NO synthase, and the increase of cGMP levels in the SO tissues by CB agonists which decreased by L-NAME show that the relaxation effects of these agonists may also partially be via increasing the NO synthesis or release.

[Effect of different doses of fentanyl and butylhyoscine on the rabbit's sphincter of Oddi]. / Efecto del fentanilo a diferentes dosis y de la butilhioscina en el esfínter de Oddi del conejo.

BACKGROUND: It was not until the advent of endoscopic retrograde cholangiopancreatography (ERCP) that Oddi's sphincter manometry was performed directly. Use of opioids for the intravenous (IV) sedation of these patients is controversial. OBJECTIVE: To evaluate with manometry the effect of fentanyl at different doses as well as the effect of butylhyoscine on the rabbit's Oddi's sphincter. METHODS: This is an experimental, randomized, double-blind study conducted in New Zealand rabbits distributed in 4 groups (control, fentanyl at doses of 1, 5 and 10 µg/kg of weight) that, after laparotomy and duodenotomy, underwent direct Oddi's sphincter manometry. The analyzed variables included sphincter pressure, wave frequency, amplitude and duration. RESULTS: The baseline measurements of the study variables did not show any differences among the groups. The administration of fentanyl at 1 µg/kg reduced Oddi's sphincter pressure compared with the baseline value (p = 0.003), while the doses of 5 and 10 µg/kg significantly increased it (p <0.0001). Butylhyoscine decreased the sphincter pressure, frequency, amplitude and duration of the waves in all the groups and antagonized the increase in pressure produced by fentanyl. CONCLUSIONS: Fentanyl at 1 µg/kg of body weight relaxes the rabbit's Oddi's sphincter and butylhyoscine can antagonize the increased pressure of the sphincter caused by fentanyl at 5 and 10 µg/kg of weight. These finding suggest a potential beneficial for the ERCP in clinical controlled trials in humans.

[Effectiveness of duspatalin therapy in the treatment and prevention of post-cholecystectomy syndrome].

Results of evaluation of the efficiency of myotropic spasmolytic Duspatalin during long-term therapy and preventive treatment of functional post-cholecystectomy syndrome are presented. The influence of the treatment on manifestations of clinical symptoms, quality of a life estimated based on a visual-analog scale, and intestinal microbiocenosis (changes in the activity of short-chain fatty acids) are discussed.

A randomized controlled trial of valdecoxib and glyceryl trinitrate for the prevention of post-ERCP pancreatitis.

BACKGROUND: Efforts to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis have been largely unsuccessful. Cyclo-oxygenase-2 enzyme-mediated inflammatory pathway has been suggested in the pathophysiology of acute pancreatitis. Glyceryl trinitrate (GTN) might prevent post-ERCP pancreatitis by relaxing the sphincter of Oddi. OBJECTIVE: To evaluate the efficacy of valdecoxib, a cyclo-oxygenase-2 inhibitor, and GTN transdermal patch for the prevention of post-ERCP pancreatitis. METHODS: Patients undergoing first ERCP procedure from October 2003 to August 2005 were randomized to receive either 20 mg intravenous valdecoxib or GTN patch (10 mg/h) at the start of ERCP, or assigned to control group. The study followed CONSORT guidelines. Primary outcome measure was frequency of post-ERCP pancreatitis in the 3 groups. RESULTS: A total of 380 patients were randomized; 121 patients in valdecoxib (group 1), 124 in GTN (group 2), and 126 in the control arm (group 3) were analyzed. There was no difference in the frequency of post-ERCP pancreatitis between the groups (12 each in groups 1 and 2, and 13 in group 3; P=0.986). None of the patients had severe pancreatitis. The frequency of post-ERCP pain and amylase levels were also similar in the 3 groups (P=0.769 and P=0.947, respectively). Pancreatic duct cannulation, cholecystectomy, difficult cannulation, and pre-cut were risk factors for pancreatitis on univariate analysis. On multivariate analysis, pancreatic duct cannulation was the only independent risk factor for pancreatitis (P≤0.001; odds ratio 5.67; 95% confidence interval: 2.76-11.63). CONCLUSIONS: Valdecoxib and GTN were not effective for the prevention of post-ERCP pancreatitis.

Botulinum toxin-induced relaxation of the sphincter of Oddi may select patients with acalculous biliary pain who will benefit from cholecystectomy.

BACKGROUND: Acalculous biliary pain may be due to gallbladder dyskinesia or sphincter of Oddi (SO) hypertension. These two etiologies are difficult to differentiate because the gallbladder ejection fraction may be low and the SO manometry results may be abnormal in both. Cholecystectomy is advised for patients with biliary dyskinesia, but it often exacerbates biliary pain for patients with SO hypertension. The biliary pain response to relaxation of the SO using botulinum toxin may indicate appropriate treatment for patients with acalculous biliary pain. METHODS: The protocol-based management of 25 patients with acalculous biliary pain and two gallbladder ejection fraction estimations less than 40% who had 100 units of botulinum toxin injected into their SO musculature to relax the sphincter has been audited. Patients whose pain was temporarily relieved after botulinum toxin injection were offered endoscopic biliary sphincterotomy, and patients who failed to experience benefit after botulinum toxin injection were assessed for laparoscopic cholecystectomy. RESULTS: Botulinum toxin was injected into the SO of 25 patients, with 11 experiencing temporary biliary pain relief. Of these patients, 10 consented to undergo endoscopic biliary sphincterotomy, with relief of biliary pain in all cases. A total of 14 patients had a negative response to botulinum toxin treatment, with 10 of these patients progressing to laparoscopic cholecystectomy, which resulted in biliary pain relief in eight cases. CONCLUSION: Botulinum toxin-induced relaxation of the SO may help to direct appropriate therapy for patients with acalculous biliary pain. The data from this study supports the establishment of a randomized clinical trial.