-
Current Neuropharmacology 2018Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD).... (Review)
Review
BACKGROUND
Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.
METHODS
Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment.
RESULTS
Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial.
CONCLUSION
New LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.
Topics: Animals; Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 28494719
DOI: 10.2174/1570159X15666170510143821 -
World Journal of Clinical Cases Dec 2018Biliary endoscopic sphincterotomy (EST) refers to the cutting of the biliary sphincter and intraduodenal segment of the common bile duct following selective cannulation,... (Review)
Review
Biliary endoscopic sphincterotomy (EST) refers to the cutting of the biliary sphincter and intraduodenal segment of the common bile duct following selective cannulation, using a high frequency current applied with a special knife, sphincterotome, inserted into the papilla. EST is either used solely for the treatment of diseases of the papilla of Vater, such as sphincter of Oddi dysfunction or to facilitate subsequent therapeutic biliary interventions, such as stone extraction, stenting, . It is a prerequisite for biliary interventions, thus every practitioner who performs endoscopic retrograde cholangiopancreatography needs to know different techniques and the clinical and anatomic parameters related to the efficacy and safety of the procedure. In this manuscript, we will review the indications, contraindications and techniques of biliary EST and the management of its complications.
PubMed: 30613665
DOI: 10.12998/wjcc.v6.i16.1073 -
Frontiers in Nutrition 2020The interaction of nutrients with the small intestine modulates postprandial cardiovascular function. Rapid small intestinal nutrient delivery may reduce blood pressure...
The interaction of nutrients with the small intestine modulates postprandial cardiovascular function. Rapid small intestinal nutrient delivery may reduce blood pressure markedly, particularly in patients with type 2 diabetes (T2DM). Postprandial hypotension occurs in ~30% of patients with longstanding T2DM, but there is little information about the cardiovascular effects of different macronutrients. We compared the blood pressure and heart rate responses to standardized intraduodenal glucose and fat infusions in T2DM. Two parallel groups, including 26 T2DM patients who received intraduodenal glucose infusion and 14 T2DM patients who received intraduodenal fat, both at 2 kcal/min over 120 min, were compared retrospectively. Blood pressure and heart rate were measured at regular intervals. Systolic blood pressure was stable initially and increased slightly thereafter in both groups, without any difference between them. Diastolic blood pressure decreased in response to intraduodenal glucose, but remained unchanged in response to lipid, with a significant difference between the two infusions ( = 0.04). Heart rate increased during both intraduodenal glucose and lipid infusions ( < 0.001 each), and the increment was greater in response to intraduodenal fat than glucose ( = 0.004). In patients with T2DM, intraduodenal fat induced a greater increase in heart rate, associated with a diminished reduction in blood pressure, when compared with isocaloric glucose. The macronutrient composition of meals may be an important consideration in T2DM patients with symptomatic postprandial hypotension.
PubMed: 33240919
DOI: 10.3389/fnut.2020.582314 -
VideoGIE : An Official Video Journal of... Jan 2021Biliary cannulation, although critical to procedural success in ERCP, can be difficult and, if unsuccessful, can lead to longer hospital stays, repeat procedures, and...
BACKGROUND AND AIMS
Biliary cannulation, although critical to procedural success in ERCP, can be difficult and, if unsuccessful, can lead to longer hospital stays, repeat procedures, and increased costs. Expertise in adjunct techniques, including access fistulotomy, can increase success rates and potentially avoid these issues. The aim of this case series is to describe the technique of access fistulotomy and illustrate key points that are important for successful biliary access.
METHODS
Three cases are reviewed in which access fistulotomy was used to achieve biliary access. The steps for the procedure are reviewed, and key technical tips and anatomic landmarks are illustrated in the video.
RESULTS
Successful biliary access is obtained using fistulotomy in 3 cases. In each case, the anatomic landmarks of the papilla and intraduodenal biliary segment are reviewed. The first case illustrates a large papilla in which initial incision followed by careful exposure reveals a clear "onion ring" structure corresponding to the bile duct. The second case requires stepwise incision, each guided by anatomic landmarks before the biliary adventitia is identified, leading to biliary cannulation. In the third case, the utility of fistulotomy in a duodenal diverticulum is illustrated. Recognition of the distorted anatomy allowed precise, careful incision leading to biliary access.
CONCLUSIONS
Access fistulotomy is an invaluable technique to aid in biliary access. Knowledge of key landmarks and careful evaluation of the incision are critical to successful biliary access when performing fistulotomy.
PubMed: 33490758
DOI: 10.1016/j.vgie.2020.10.005 -
Archives of Pathology & Laboratory... Mar 2009A variety of nonneoplastic conditions may form pancreatic masses that mimic carcinoma. Approximately 5% to 10% of pancreatectomies performed with the clinical diagnosis... (Review)
Review
CONTEXT
A variety of nonneoplastic conditions may form pancreatic masses that mimic carcinoma. Approximately 5% to 10% of pancreatectomies performed with the clinical diagnosis of pancreatic cancer prove on microscopic evaluation to be pseudotumors.
OBJECTIVES
To illustrate the clinical and pathologic characteristics of the 2 most frequent pseudotumoral inflammatory conditions, autoimmune pancreatitis and paraduodenal pancreatitis, and describe the criteria that may be useful in the differential diagnosis versus pancreatic carcinoma.
DATA SOURCES
Recent literature and the authors' experience with the clinical and pathologic characteristics of autoimmune pancreatitis and paraduodenal pancreatitis.
CONCLUSIONS
The knowledge of the clinical, radiologic, and pathologic findings in both autoimmune pancreatitis and paraduodenal pancreatitis is crucial in making the correct preoperative diagnosis. Autoimmune pancreatitis, which occurs in isolated or syndromic forms, is characterized by a distinctive fibroinflammatory process that can either be limited to the pancreas or extend to the biliary tree. Its correct preoperative identification on biopsy material with ancillary immunohistochemical detection of dense immunoglobulin G4-positive plasma cell infiltration is possible and crucial to prevent major surgery and to treat these patients with steroid therapy. Paraduodenal pancreatitis is a special form of chronic pancreatitis that affects young males with a history of alcohol abuse and predominantly involves the duodenal wall in the region of the minor papilla. Pathogenetically, the anatomical and/or functional obstruction of the papilla minor, resulting from an incomplete involution of the intraduodenal dorsal pancreas, associated with alcohol abuse represents the key factor. Endoscopic drainage of the papilla minor, with decompression of the intraduodenal and dorsal pancreas, might be considered in these patients.
Topics: Diagnosis, Differential; Granuloma, Plasma Cell; Humans; Pancreatic Neoplasms; Pancreatitis
PubMed: 19260749
DOI: 10.5858/133.3.439 -
World Journal of Gastroenterology Aug 2022The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has...
BACKGROUND
The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.
AIM
To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.
METHODS
Twenty diabetic rats were randomly allocated to the sham ( = 10) and DJB ( = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.
RESULTS
The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.
CONCLUSION
DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.
Topics: Animals; Rats; AMP-Activated Protein Kinases; Bile Acids and Salts; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Duodenum; Gastric Bypass; Glucose; Jejunum; Pyruvates; RNA, Messenger; Sirtuin 1; Streptozocin
PubMed: 36159018
DOI: 10.3748/wjg.v28.i31.4338 -
Journal of Neurology, Neurosurgery, and... Jun 1989The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity... (Review)
Review
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.
Topics: Circadian Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Levodopa; Parkinson Disease; Psychomotor Performance
PubMed: 2666577
DOI: 10.1136/jnnp.52.suppl.29 -
Parasite (Paris, France) 2014Immunodeficiency, particularly antibody deficiency, predisposes to increased intensity and persistence of Giardia infections. Giardia-infected immunocompetent hosts... (Review)
Review
Immunodeficiency, particularly antibody deficiency, predisposes to increased intensity and persistence of Giardia infections. Giardia-infected immunocompetent hosts produce serum and intestinal antibodies against Giardia trophozoites. The number of Giardia muris trophozoites, in mice with G. muris infection, is reduced by intra-duodenal administration of anti-G. muris antibody. Giardia intestinalis antigens that are recognised by human anti-trophozoite antibodies include variable (variant-specific) and invariant proteins. Nitric oxide (NO) appears to contribute to host clearance of Giardia trophozoites. Arginine is a precursor of NO and is metabolised by Giardia trophozoites, possibly reducing its availability for generation of NO by the host. Work with mice suggests that T lymphocytes and interleukin-6 (IL-6) contribute to clearance of Giardia infection via mechanisms independent of antibodies.
Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Disease Models, Animal; Giardia; Giardia lamblia; Giardiasis; Host-Parasite Interactions; Humans; Immunization, Passive; Immunocompetence; Membrane Proteins; Mice; Nitric Oxide; Protozoan Proteins; Species Specificity
PubMed: 25347704
DOI: 10.1051/parasite/2014056 -
The Journal of Clinical Endocrinology... Aug 2023Premenopausal women are at a lower risk of type 2 diabetes (T2D) compared to men, but the underlying mechanism(s) remain elusive. The secretion of the incretin hormones,...
CONTEXT
Premenopausal women are at a lower risk of type 2 diabetes (T2D) compared to men, but the underlying mechanism(s) remain elusive. The secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), from the small intestine is a major determinant of glucose homeostasis and may be influenced by sex.
OBJECTIVES
This study compared blood glucose and plasma insulin and incretin responses to intraduodenal glucose infusions in healthy young males and females.
DESIGN
In Study 1, 9 women and 20 men received an intraduodenal glucose infusion at 2 kcal/min for 60 minutes. In Study 2, 10 women and 26 men received an intraduodenal glucose at 3 kcal/min for 60 minutes. Venous blood was sampled every 15 minutes for measurements of blood glucose and plasma insulin, GLP-1 and GIP.
RESULTS
In response to intraduodenal glucose at 2 kcal/min, the incremental area under the curve between t = 0-60 minutes (iAUC0-60min) for blood glucose and plasma GIP did not differ between the 2 groups. However, iAUC0-60min for plasma GLP-1 (P = 0.016) and insulin (P = 0.011) were ∼2-fold higher in women than men. In response to intraduodenal glucose at 3 kcal/min, iAUC0-60min for blood glucose, plasma GIP, and insulin did not differ between women and men, but GLP-1 iAUC0-60min was 2.5-fold higher in women (P = 0.012).
CONCLUSION
Healthy young women exhibit comparable GIP but a markedly greater GLP-1 response to intraduodenal glucose than men. This disparity warrants further investigations to delineate the underlying mechanisms and may be of relevance to the reduced risk of diabetes in premenopausal women when compared to men.
Topics: Male; Female; Humans; Incretins; Glucose; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Insulin
PubMed: 36987568
DOI: 10.1210/clinem/dgad176 -
American Journal of Physiology.... Feb 2015Intraduodenal infusion of lipid or protein potently reduces subsequent energy intake. There is evidence that the underlying mechanisms differ significantly between the... (Comparative Study)
Comparative Study
Intraduodenal infusion of lipid or protein potently reduces subsequent energy intake. There is evidence that the underlying mechanisms differ significantly between the two nutrients. While intraduodenal lipid stimulates glucagon-like peptide-1 and CCK much more than protein, the release of insulin and glucagon is substantially greater in response to protein. Ghrelin and PYY are both involved in short-term regulation, while leptin is a long-term regulator, of energy balance; the acute effects of nutrients on leptin release are unclear. We investigated the comparative effects of intraduodenal lipid and protein on plasma ghrelin, PYY, and leptin concentrations. Thirteen lean, young men received 90-min intraduodenal infusions of protein (whey hydrolysate) or lipid (long-chain triglyceride emulsion) at a rate of 3 kcal/min, or saline control, on three separate days. Blood samples were collected at baseline and regularly during infusions. Both lipid and protein potently suppressed plasma ghrelin compared with control (both P < 0.001), with no difference between them. While both lipid and protein stimulated plasma PYY (P < 0.001), the effect of lipid was substantially greater than that of protein (P < 0.001). Neither intraduodenal lipid nor protein affected plasma leptin. In conclusion, intraduodenal lipid and protein have discrepant effects on the release of PYY, but not ghrelin. When considered with our previous findings, it appears that, with the exception of ghrelin, the energy intake-suppressant effects of lipid and protein are mediated by different mechanisms.
Topics: Adolescent; Adult; Cross-Over Studies; Dietary Fats; Dietary Proteins; Double-Blind Method; Duodenum; Eating; Energy Metabolism; Ghrelin; Healthy Volunteers; Humans; Leptin; Male; Milk Proteins; Peptide YY; Postprandial Period; Protein Hydrolysates; Time Factors; Triglycerides; Whey Proteins; Young Adult
PubMed: 25568079
DOI: 10.1152/ajpregu.00504.2014