Cholecystokinin and cholecystokinin-A receptor: An attractive treatment strategy for biliary dyskinesia?

Biliary dyskinesia is a relatively common gastrointestinal disease that is increasing in incidence as living standards improve. However, its underlying pathogenesis remains unclear, hindering the development of therapeutic drugs. Recently, "Expression and functional study of cholecystokinin-A receptors on the interstitial Cajal-like cells of the guinea pig common bile duct" demonstrated that cholecystokinin (CCK) regulates the contractile function of the common bile duct through interaction with the CCK-A receptor in interstitial Cajal-like cells, contributing to improving the academic understanding of biliary tract dynamics and providing emerging directions for the pathogenesis and clinical management of biliary dyskinesia. This letter provides a brief overview of the role of CCK and CCK-A receptors in biliary dyskinesia from the perspective of animal experiments and clinical studies, and discusses prospects and challenges for the clinical application of CCK and CCK-A receptors as potential therapeutic targets.

Diagnostic stringency and healthcare needs in patients with biliary dyskinesia.

AIM: We have recently shown an increase in cholecystectomies for biliary dyskinesia. Based on these results, we hypothesized that diagnostic criteria are less stringently applied which may contribute to ongoing resource utilization. METHODS: Using billing codes, patients seen for biliary dyskinesia were identified and data were extracted from the electronic medical record to confirm the diagnosis, obtain demographic and clinical data and assess resource utilization 1 year prior to and after cholecystectomy. RESULTS: A total of 972 patients were identified, with 894 undergoing cholecystectomy. In 259 patients, symptoms had started <3 months prior to evaluation. Functional gallbladder imaging revealed a mean gallbladder ejection fraction of 23.1 ± 0.7 %; of the patients undergoing surgery, 116 had a normal gallbladder ejection fraction. Sufficient up data for pre- and post-operative assessment of resource utilization was available for 368 patients. Emergency room (ER) visits decreased from 0.86 ± 0.07 to 0.69 ± 0.03 (P < 0.05), while hospitalization rates remained unchanged after surgery. Patients not meeting consensus criteria for the diagnosis of biliary dyskinesia were more likely to use opioids and have ER visits prior to and after cholecystectomy. Using multiple logistic regression benzodiazepine use, migraine history and prior ER visits independently predicted postoperative resource utilization. CONCLUSIONS: Our data demonstrate that a significant number of patients undergo cholecystectomy for biliary dyskinesia, even though they do not meet currently accepted diagnostic criteria. While healthcare resource utilization drops within the first year after surgery, ER visits and hospitalizations remain common, suggesting a more limited benefit of surgical approaches in these patients.

[Mebeverina drugs in the treatment of functional disorders of the digestive system].

Despite the identical content of mebeverine hydrochloride, Duspatalin and Niaspam, produced by different technological processes, can't be considered interchangeable as they are known to have different clinical effect in case of various functional diseases of alimentary organs. Duspatalin is effective in relieving biliary disfunction symptoms, Oddy's sphincter hypertonicity in particular, but has little effect on intestinal dyskinesia. Niaspam is known to have little effect on biliary dyskinesia, but has a prominent positive clinical effect on intestinal dyskinesia.

[Significance of biliary dysfunction in the pathogenesis of gallstone disease].

The paper shows the role of biliary dysfunction in the formation of biliary sludge. Found that among all motor dysfunction themost common is reduction of contractile function of the gallbladder (in 63.3% of cases), which is combined with 73.2% Oddi's sphincter hypertonus. T The combination of ursodeoxycholic acid (UDCA) with mebeverine has a better effect than monotherapy with UDCA, as increases the frequency of relief of biliary dyspepsia symptoms, normalizes the biliary tract functional status and 95% of cases leads to the elimination of biliary sludge.

Biliary Dyskinesia: Fact or fiction?

Nearly 20,000 pediatric patients undergo cholecystectomy annually, and abnormal gallbladder emptying ("biliary dyskinesia") has replaced cholelithiasis as the leading indication for this operation in the USA. Nonetheless, patients with abnormal gallbladder emptying nuclear medicine scans do not uniformly benefit from cholecystectomy. This article reviews the available data on presentation, workup and treatment of patients with abnormally low and high rates of gallbladder emptying.

The use of tenoten preparation in complex therapy of hypomotoric biliary dyskinesia.

A positive effect of tenoten on the course of biliary dyskinesia in patients with anxiety and depressive disorders was demonstrated. Tenoten can be recommended for the treatment of functional cholangio-pancreatoduodenal motility disturbances.

[Vegetotropic therapy and hypobaric hypoxic adaptation in gallbladder motor dysmotility].

The study of 67 chronic biliary patients (36 - gallbladder dysfunction, 25 acalculuous cholecystitis, 6 - cholelithiasis) was revealed their functional dysadaptation characterized by gallbladder dysmotility and autonomic dysfunction. Vegetotropic therapy (Propranolol, Metoclopramid, Atropine) according to the autonomic regulation activity has advantages in correction of the gallbladder dysmotility in comparison to the routine pharmacotherapy. Hypobaric hypoxic adaptation results in the increase of gallbladder emptying that opens perspectives for the non-pharmacological correction of the gallbladder hypokinetic dyskinesia.

Innervation of the sphincter of Oddi: physiology and considerations of pharmacological intervention in biliary dyskinesia.

The sphincter of Oddi is a small sphincter which is strategically placed at the junction of the bile duct and pancreatic duct with the duodenum. It regulates the flow of bile and pancreatic juice into the duodenum and prevents reflux of duodenal contents into the ducts. The structure of the sphincter of Oddi differs from species to species and consequently its physiological action varies in different species. Anatomical and immunohistochemical investigations have demonstrated that the sphincter of Oddi is richly innervated by cholinergic, adrenergic and peptidergic neurons. In addition, neural connections exist between the sphincter, gallbladder and proximal gastrointestinal tract. These nerves in addition to hormones are important in the control of sphincter of Oddi motility and function. The normal human sphincter of Oddi is characterized by prominent phasic contractions which are superimposed on a modest basal pressure. These contractions are present throughout the interdigestive period. The contractions and basal pressure are inhibited by ingestion of a meal or infusion of cholecystokinin octapeptide, thus enhancing the flow of bile and pancreatic juice into the duodenum. Sphincter of Oddi dysfunction has been described in patients who present with recurrent biliary type pain and no evidence of a structural cause for the pain. Motility disorders characterized as an elevated basal pressure, rapid contraction frequency, paradoxical response to cholecystokinin octapeptide or excess of retrograde contractions have been identified. A number of pharmacologically active substances have been used in an attempt to treat these patients. Such pharmaceuticals include nitrites, Ca2+ channel blockers and smooth muscle relaxants. Their effect is transient and side effects relating to cardiovascular actions preclude their longterm use. Division of the sphincter either endoscopically or by open operation has been demonstrated by prospective clinical trials to be the most efficacious treatment for patients with a stenosed sphincter manometrically demonstrated by a high basal pressure. Improved understanding of the controlling mechanisms of sphincter of Oddi motility and the pathophysiology of sphincter of Oddi dysfunction should assist in the development of effective pharmacotherapy for these disorders.

[Use of grandaxin in hypermotor dysfunction of the biliary ducts in young people].

GOAL OF THE STUDY: Complex study of psychovegetative disorders at hypermotor dysfunction of biliary ducts in young people and correction of these disorders with the help of grandaxin. MATERIAL AND METHODS OF STUDY: Thirty-five patients with hypermotor dysfunction (biliary dyskinesia). The control group comprised 33 patients of the same sex and age. The mental status was assessed with the use of BMQP (brief multifactorial questionnaire for personality examination), Spielberger, Eysenck and Heck-Hess tests. The cardiac rate mathematical analysis method by R.M. Bayevsky and Wein-Solovyova tables were used to study the vegetative nervous system function. Vegetative disorders were corrected with the help of grandaxin. STUDY RESULTS: The mental status of patients with biliary dyskinesia differed reliably from that in the control group. When the vegetative system was examined in the biliary dyskinesia group in the state of rest, the parasympathetic reaction was greatly increased at the load, being greater than in the control group. CONCLUSION: When biliary dyskinesia is treated, it is recommended to correct psychovegetative disorders with the help of an original drug named grandaxin.

Studies on papillary function and effect of prifinium bromide and other antispasmodics on motility of the papillary region (sphincter of Oddi) in humans.

We determined endoscopically the motility of the papillary region in humans, using a pressure sensor devised in our department. The subjects were 184 patients with various diseases. Prifinium bromide and four other antispasmodics were given to 60 of the 184 patients, and their effects were investigated. In 41 (85%) of the 48 patients with chronic gastritis, regular wave patterns were noted. In 35 (85%) of the 41 patients with diseases of the biliary tract and papillary region, in nine (82%) of the 11 patients with pancreatic diseases, and in six (67%) of the nine patients with liver diseases, irregular wave patterns were observed. It was postulated that a high incidence of papillary dysfunction accompanies biliary and pancreatic diseases. Additionally, it was concluded that prifinium bromide has as potent an effect on motility of the papillary region as does a massive dose (40 mg) of hyoscine N-butylbromide.

The effect of cisapride on gallbladder contractility in type II diabetic patients.

BACKGROUND/AIMS: To investigate whether diabetics have altered gallbladder motility, and whether cisapride has any effect on gallbladder motility in these patients. The factors associated with abnormal gallbladder contractility, and with the effects of cisapride on gallbladder contractility in diabetics were also evaluated. METHODOLOGY: The gallbladder contractility parameters of 20 diabetics and 20 controls were assessed by real time ultrasonography. The same measurements were made after cisapride treatment in diabetics. RESULTS: Fasting gallbladder volume and residual gallbladder volume were statistically higher in the diabetic group than in the controls (P = 0.018 and P = 0.022, respectively). Multivariate analysis also showed a significant association between fasting gallbladder volume and existing diabetes (P = 0.0002). There was a significant positive correlation between level of hemoglobin A1c and fasting gallbladder volume (r = 0.48, P = 0.031). Responders to cisapride treatment had significantly higher hemoglobin A1c levels than nonresponders (6.6 +/- 1.3 vs. 9.1 +/- 1.8, respectively; P = 0.004). Logistic multiple regression analysis revealed that hemoglobin A1c level was the only independent factor that was predictive for efficacy of cisapride treatment. CONCLUSIONS: This study demonstrates that diabetics have impaired gallbladder contractility, and that control of diabetes is predictive for gallbladder contractility and response to cisapride therapy in these patients.

[Effects of fenoverine on biliary kinetics evaluated by hepatobiliary scintigraphy with 99mTc-Br-IDA]. / Effetti della fenoverina sulla cinetica biliare valutata con scintigrafia epatobiliare con 99mTc-Br-IDA.

Hepatobiliary scintigraphy was used to evaluate the action of fenoverine in 16 patients suffering from dyskinesia of the biliary tract; the drug was administered in doses of 300 mg per day per os for 20 days, the patients being subjected to hepatobiliary scintigraphy before and after treatment. The following parameters--accurate indicators of the motor coordination of the biliary tract--were evaluated: tracer appearance time in the gallbladder (Tc) and in the intestine (Ti). After treatment there was a normalization of these two parameters which initially were extended. Statistical analysis showed a highly significant reduction in these times. Stress is laid on the importance of hepatobiliary scintigraphy in the diagnosis of biliary dyskinesia and on the effectiveness of fenoverine in the treatment of this conditions.

[Effects of tiropramide on gallbladder emptying in patients with a dyspeptic syndrome associated with biliary dyskinesia]. / Effetti della Tiropramide sullo svuotamento colecistico in portatori di sindrome dispeptica correlata a discinesia biliare.

Thirty patients with biliary dyskinesia were treated with 300 mg/t.i.d. of Tiropramide for 15 days. The statistical evaluation showed a significant reduction of symptoms, an increase (p less than 0.001) of volumes and an improvement (p less than 0.001) of gallbladder emptying.

[Using botulinum toxin type A in the gastrointestinal tract]. / Einsatz von Botulinumtoxin A im Gastrointestinaltrakt.

BACKGROUND: Botulinum toxin (BTX) is an extremely potent poison which interacts selectively with cholinergic neurons to inhibit the release of neurotransmitters. Local intrasphincteric injection of BTX has been suggested as possible therapy for several spastic disorders of the gastrointestinal tract. INDICATIONS: There is good evidence for the clinical benefit of BTX injection as an alternative treatment for achalasia and chronic anal fissures. Other possible indications for BTX injection such as sphincter of Oddi dyskinesia or cervical achalasia remain to be further established. BTX injection showed no severe side effects when compared to other interventional or operative treatment alternatives. However, the effect of BTX injection lasts only for several months and is fully reversible. The time-limited effect of BTX is a disadvantage in the treatment of achalasia. By contrast, the limited effect is advantageous in the treatment of chronic anal fissures as the normal function is restored after the lesion has healed and the BTX effect disappeared. The use of BTX has added a new therapeutic concept with few side effects to our interventional methods. When applied critically, this method can be used with benefit for the treatment of our patients.

[Treatment of bile duct diseases. Dyskinesias. Chronic inflammation]. / Tratamento das doenças das vias biliares. Discinesias. Inflamaçãi crônica.

The approach to the integrated diagnosis of the patient with biliary tract diseases is reviewed as a basis for the appropriate treatment, taking into account the functional disturbances and the organic elements including malformation, inflammation, infection, gallstone and neoplasia. The role of impaired emptying of the gallbladder is emphasized. This condition may give origin to inflammation of the gallbladder is emphasized. This condition may give origin to inflammation of the gallbladder which is caused by the irritative action of concentrated bile acids as a consequence of the stagnated bile in the gallbladder with poor emptying. Other consequences of bile stagnation in the gallbladder is gallstone formation and biliary infection by bacterias. Thus, increase of gallbladder emptying and of bile production are advised in the treatment of biliary diseases. Such two effects can be obtained by the diet using adequate amounts of vegetables, oils and eggs and by drugs such as choleretics. A new choleretic drug-the cicloxilic acid-was used in 102 patients, 48 out of them with gallstone and 54 without lithiasis. The following three actions of this drug were recorded: a decrease of gastrointestinal gaseousness; a decrease of abdominal discomfort and soreness, and a mild laxative effect with stool of less consistency.

[Management of Oddi sphincter dyskinesis. Results of drug therapy and sphincterotomy]. / Az Oddi-sphincter dyskinesis kezelése. A gyógyszeres terápia és a sphincterotomia eredményei.

UNLABELLED: In a retrospective evaluation, the outcome of the long term treatment of the sphincter of Oddi dyskinesia (OD, type III. dysfunction) has been analysed. PATIENTS AND METHOD: Therapeutic results of 64 cholecystectomised patients with OD were evaluated by means of regular follow-up and questionnaire filled in either by the patients or their practitioners. RESULTS: Conservative treatment (nitroglycerin, calcium channel blocker or both) resulted in symptom-free condition or improvement with 53% of the patients (37/64). Out of 27 patients whose condition did not improve by combined drug therapy, in 20 cases endoscopic sphincterotomy (EST) and in 1 case transduodenal sphincterotomy were performed. Having followed sphincterotomy, out of 21 patients only 9 became symptom-free and 5 improved. CONCLUSIONS: Therapeutic benefit of sphincter relaxants fail in nearly half of the cases with OD, and even sphincterotomy can lead to symptomless condition only in a portion of OD. Regarding the high incidence of complications following EST in OD, it can only be recommended after failure of the conservative therapy in correctly diagnosed cases. The results emphasise a need for a prospective randomised controlled clinical study to seek for the optimal therapeutic regimen.

[Galstena efficacy in patients with biliary dyskinesia, chronic cholecystitis and cholelithiasis]. / "Galstena" u patsientov s diskineziei zhelchnovyvodiashchikh putei, khronicheskim kholetsistitom i zhelchno-kamennoi bolezn'iu.

The response of inflammation, bile secretion, lipid metabolism, LDL sensitivity to oxidation was studied in patients with bile duct dyskinesia (BDD), chronic cholecystitis (CC) and cholelithiasis (CL) before and after a course of therapy with galstena. The treatment improved general condition in 90% of the patients, dyspeptic symptoms relieved or stopped. Galstena relieved general or local inflammation, reduced mean levels of total cholesterol and LDL cholesterol, raised HDL cholesterol. In patients with BDD and cholelithiasis galstena did not change normal sensitivity of LDL to oxidation. A galstena course in BDD and CC patients significantly diminished bile lithogenicity and improved gall bladder contractility.

[Use of tykveol in the treatment of impaired biliary tract function in patients with chronic non-calculous cholecystitis]. / Primenenie tykveola v lechenii narushenii funktsional'nogo sostoianiia zhelchevyvodiashchikh putei u bol'nykh khronicheskim nekal'kuleznym kholetsistitom.

The therapeutic efficacy of tykveol was evaluated in 22 patients with chronic non-calculous cholecystitis and/or dyskinesia of the biliary tract (BT) concurrent with gallbladder deformity (GD). Supplementation of tykveol to the combined therapy in the patients with chronic non-calculous cholecystitis concurrent with GD was shown to exert a pronounced therapeutic effect. This caused positive changes in clinical symptoms and BT function, diminished the lithogenic propertes of bile. With the use of tykveol, recovery of neurohumoral regulation is an important factor that improves biliary tract function, as evidenced by decreased gastrin secretion.