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Dúvidas [email protected] Site www.gilbertodenucci.com Arquivo Medicamentos que atuam na motilidade intestinal Mechanism of action of laxatives Bulk laxatives osmotic laxatives Mg 2+ lactulose H2O sterculia salt bran ispaghula swells and distends colon H2O cholecystokinin stimulates motility increases intestinal fluid secretion fecal softener docusate H2O stimulates enteric nervous system stimulante (irritant) laxatives senna danthron area postrema (chemoreceptor trigger zone) The major soft palatene visceral and epiglottis central trachea structures involved in phrenoesophageal ligament diaphragm the emetic pylori sphincter reflex vomiting center pharynx esophagus cardiac spincter fundus duodenal bulb body cardia duodenum pyloric antrum Causes and incidence of nausea and vomiting Alcohol 15% food poisoning 9.5% binge eating 7.4% migraine 4% induced vomiting 3.2% food allergy 2.7% stress 2% travel 1.2% Causes and incidence of nausea and vomiting nausea vomiting Percentage of respondants 80 60 40 20 0 18-30 31-60 >60 18-30 31-60 >60 The frequency of sickness in pregnancy during the first trimester Percentage of pregnant women 50 nausea 40 Daily Weekly Less often 30 20 10 0 4 6 8 12 Duration of pregnancy (weeks) The frequency of sickness in pregnancy during the first trimester Percentage of pregnant women 50 vomiting 40 Daily Weekly Less often 30 20 10 0 4 6 8 12 Duration of pregnancy (weeks) The major emetic stimuli, pathways, and structures mediating the emetic reflex and nausea. layrinth endogenous or exogenous toxins or drugs VIII nerve vestibular nucleous in the blood stream or cerebrospinal fluid cerebellum chemoreceptor trigger zone in area postrema in the gut vagus and/or sympathetic nerves mechanical stimuli higher centers visual olfactory emotional anticipatory pharynx vomiting center: effector nuclei coordinating the emetic reflex salivary gastroinstestinal respiratory centers pain retching and vomiting nausea Cortex inferior frontal gyrus cardiovascular system H1 area postrema nucleus tractus 5-HT3solitarius DA ACh Chemical transmitters mediating emetic stimuli vagal/splanchic afferent nerves NT S VC circulation gut capillary 5-HT afferent vagus nerve 5-HT EC capillary platelets lumen PGs kinis inflammation GI irritation chemotherapy, radiation, Infection, drugs Stimulus Pain, repulsive sights and smells, emotional factors Input Integration Sensory afferents and CNS pathways H1-receptor antagonists, muscarinic receptor antagonists Motion sickness Dopamine antagonists, 5-HT3 antagonists Nerves to somatic and visceral receptors CTZ (D2 and 5-HT3 receptors) Vomiting centre (mACh receptors) Blood Release of emetogenic agents (5-HT, prostanoids, free radicals) Stimuli from pharynx and stomach Higher centres - Labyrinth Vestibular nuclei (H1 and mACh receptors) Endogenous toxins, drugs Output Visceral afferents (5-HT3 receptors?) 5-HT3 anatagonists - Nucleus of the solitary tract (mACh and H1 receptors - Muscarinic receptor antagonists - H1-receptor antagonists Hyoscine Antihistamines Motion Vestibular apparatus (ear)(ACh, H1) Metoclopramide, Domperidone increase gastric emptying rate and oesophageal tone 5-HT3 anatagonists Vomiting centre (medullar) (ACh, H1, 5-HT3) Chemoreceptor trigger zone (4th ventricle)(D2) Efferent Afferent Metoclopramide, 5HT3 antagonists decrease sensitivity Phenothiazines Butyrophenones Metoclopramide Domperidone Antihistamines Receptors in pharynx pylorus, bowel, and biliary tree Elevation of cardia, closure of pylorus, contraction of abdominal muscles Vomiting Vagus, sympathetic, phrenic, and other nevers Other stimuli, e.g. emetics Commonly used laxatives 1 - Bulk-forming agents Bran Ispaghula husk Methylcellulose Sterculia 3 - Gastrointestinal stimulants Senna Anthraquinones Danthron Sodium picosulfate Bisacodyl Castor oil 2 - Faecal Softeners and lubricants Arachis oil Dioctyl sodium sulfosuccinate 2 - Osmotic laxatives Lactulose Magnesium salts Sodium salts Drugs used in the symptomatic treatment of diarrhoea 1 - Drugs that alter gastrointestinal molity Codeine Diphenoxylate (combined with atropine in Lomotil®) Loperamide Morphine 2 – Fluid adsorbents Kaolin 3 – Fluid absorbents Bulk-forming agents 4 – Drugs used in specific circumstances Indomethacin (radiation-induced enteritis) Cholestyramine (diarrhoea due to excess bile acids Pancreatic enzymes (pancreatic malabsorption) Daily Secretion of Intestinal Juices Daily Volume (ml) pH • Saliva 1000 6.0 – 7.0 • Gastric secretion 1500 1.0 – 3.5 • Pancreatic secretion 1000 8.0 – 8.3 • Bile 1000 7.8 • Small intestine secretion 1800 7.5 – 8.0 • Brunner’s gland secretion 200 8.0 – 8.9 • Large intestinal secretion 200 7.5 – 8.0 TOTAL 6700 Postulated mechanism for the secretion of hydrochlric acid Extracellular fluid Parietal cell CO2 CO2 HCO3 HCO3- K+ Lumen of canaliculus H2 O H+ (155 mEq/L) CO2 + OH- + H+ P K+ K+ K+ (15 mEq/L) Na+ Na+ Na+ (3 mEq/L) P Na+ P Cl- H2 O Cl- Cl(Osmosis) P Cl- (173 mEq/L) H2 O Secretion of isosmotic sodium bicarbonate solution by the pancreatic ductules and ducts Bloo d Ductule cells Na+ Na+ H+ H+ Lumen Na+ HCO3 HCO3(Active transport) (Active transport) H2CO3 (Carbonic anyhydrase) H2O CO2 H2 O CO2 H2O Vagus nerve Cholesresis Cholecystokinin Secretin Stimulate secretion Stimulate secretion Hormones of the Gastrointestinal Tract HCI Inhibit secretion Stimulated motility Food acid Food distention Inhibit motility Secretin Enzymes Water, bicarbonate Pancreas GIP Food fat Food fat Motilin Neuroendocrine cel Stimulates smooth muscle Thick line indicates primary action Thin lin indicates secondary action Hormones of the Gastrointestinal Tract Hormone Neuroendocrine Cell Type and Location Gastrin G cell Stomach, duodenum Vagus, destention, amino acids Stimulate HCl secretion Inhibit gastric emptying Secretin S cell Duodenum Acid Stimulate pancreatic ductal cell H2O and HCO3- secretion Inhibit gastric secretion, inhibit gastric motility, and stimulate bile duct secretion of H2O and HCO3- Cholecystokinin I cell Duodenum, jejunum Fat, vagus Stimulate enzyme secretion by pancreatic acinar cells and contract the gallbladder Inhibit gastric motility GIP K cell Duodenum, jejunum Fat Inhibit gastric secretion and motility Stimulate insulin secretion Motilin M cell Duodenum, jejunum Stimuluis for Secretion Primary Action Increase motility and initiate the MMC Other Action Drugs used for the tratment of constipation A variety of bulk-forming laxatives including bran, ispaghula, sterculia, methylcellulose Senna Minimal absorption: action takes up to 12 hours given orally and less than 2 hours rectally Bisacodyl Administered orally or rectally Minimal absorption but relatively quick action after 6-8 hours orally but less than 60 minutes rectaly Lactulose Poorly absorbed orally and broken down to active acids in the colon Takes 1-2 days to act Docusate Surfactant action. Minimally absorbed. Acts in up to 3 days Magnesium sulfate Acts within 6 hours. Up to 30% absorbed. Renal elimination Danthron An animal carcionogen restricted for use in terminally ill Liver damage Sodium picosulfate Used only as a preoperative bowel preparation Int. Pharmacology – Chapter 21 Drugs and inflammatory bowel disease ● Aminosalicylates such as mesalamine and olsalazine maintain remission ● Glucocorticosteroids are effective for acute relapse of the disease ● Poorly absorbed glucocorticosteroids (e.g. budesonide) have little effect on the hypothalamic-pituitary-adrenal axis ● Nonsteroidal anti-inflammatory drugs exarcerbate inflammatory Int. Pharmacology – Chapter 21 Mechanism of action of some drugs that cause jaundice Mechanism Hemolysis bilirubin production) Drug Antimalarials Sulfonamides Aspirin Phenacetin Cephalosporins Methyldopa Commen Occurs in people with glucose-6- (increased phosphate dehydrogenase (G6PD) Immunologic basis Altered Hepatic bilirubin uptake Rifampin Hepatotoxicity Caebon tetrachloride Acetaminophen overdose Tetracycline Treat with N-acetylcysteine Avoid in pregnancy Diffuse hepatocellular damage Tricyclic antidepressants Isoniazid Uncommon Related to dose and patient’s age Intrahepatic Cholestasis Anbolic steroids Phenothiazines Erythromycin Int. Pharmacology – Chapter 21 Incidence probably not related to type of salt used (e.g. Estolate) Causes and incidence of nausea and vomiting 9,5% 7,4% Binge eating Migraine 4% 3,2% Induced vomiting Food allergy travel 2,7% 2% 1,2% Percentage of respondants Food poisoning Stress 80 15% Acohol nausea vomiting 18-30 31-60 >60 18-30 31-60 >60 60 40 20 0 Age (year) Int. Pharmacology – Chapter 21 Pivotal events nausea and emesis ● Relaxantion of the esophagus, esophageal sphincter, cardiac sphincter, and fundus and body of the stomach ● Contraction of the upper small intestine and pyloric stomach, emptying their contents int the relaxed stomach ● Deep inspiration and closure of the glottis and raising of the soft palate ● Rhythmic contraction of the diaphragm and abdominal muscles to compress the stomach and evacuate its contents via the mouth Int. Pharmacology – Chapter 21 The frequency of sickness in pregnancy during the first trimester 50 50 nausea vomiting 40 Percentage of pregnant women Percentage of pregnant women 40 30 20 10 0 4 6 8 Duration of pregnancy (weeks) Int. Pharmacology – Chapter 21 20 10 0 4 12 Daily 30 6 8 12 Duration of pregnancy (weeks) Weekly Less often Emetic potential of chemotherapeutic drugs Severely emetogenic in almost all patients Moderately emetogenic Cisplatin Mitomycin C 5-Fluorouracil Mustine Procarbazine Cytarabine Cyclophosphamide Nitrosoureas 6-Mercaptopurine Least emetogenic Dacarbazine Bleomycin Doxorubicin Vinblastine Doxorubicin Vinsristine Int. Pharmacology – Chapter 21 Major stimuli of nausea and vomiting ● Gastrointestinal irritation ● Motion sckness ● Hormone disturbance ● Intracranial pathology ● Metabolic disieders ● Psychogenic factors ● Pain ● Drugs and radiation ● Endogenous Toxins Int. Pharmacology – Chapter 21 The number of women who reported sickness with oral contraceptives, travel, or migraine and the relationship to vomiting in pregnancy Pregnancy sickness Oral contraceptive sickness Travel sickness Migraine sickness Vomiting 30 (70%) 77 (63%) 45 (65%) No vomiting 13 (30%) 46 (37%) 24 (35%) Int. Pharmacology – Chapter 21 The major emetic stimuli, pathways, and structures mediating the emetic reflex and nausea labyrinth Endogenous or oxgenous toxins or drugs VIII nerve In the blood stream or cerebrospinal fluid Vstibular nucleus Chemoreceptor trigger zone in area postrema In the gut Mechanical stimuli Vagus and/or sympathetic nerves cerebellum Higher centers visual olfactory emotional anticipatory Vomiting center: effector nuclei coordinating the emetic reflex Salivary gastrointestinal respiratory centers Pharynx Pain Int. Pharmacology – Chapter 21 Retching and vomiting nausea Cardiovascular system Cortex inferior frontal gyrus Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, July 2007, 61, 7, 1181–1187 Medications known to cause chronic constipation Prescription Over-the-Cou nter Opiates Antacids, especially those containing calcium Anticholinergic agents Calcium supplements Tricyclic antidepressants Iron supplements Calcium channel blockers Antidiarrheal agents Antiparkinsonian agents NSAIDs Sympathomimetic agents Antipsychotic agents Diuretics Antihistamines Lubiprostone: Chloride Channel Activator for Chronic Constipation - Clinical Therapeutics/Volume 28, Number 12, 2006 Selected laxatives, their usual doses, and adverse effects Lubiprostone: Chloride Channel Activator for Chronic Constipation - Clinical Therapeutics/Volume 28, Number 12, 2006 Selected laxatives, their usual doses, and adverse effects (cont) Lubiprostone: Chloride Channel Activator for Chronic Constipation - Clinical Therapeutics/Volume 28, Number 12, 2006 Selected laxatives, their usual doses, and adverse effects (Cont) Lubiprostone: Chloride Channel Activator for Chronic Constipation - Clinical Therapeutics/Volume 28, Number 12, 2006 Summary of efficacy data for various classes of laxatives Lubiprostone: Chloride Channel Activator for Chronic Constipation - Clinical Therapeutics/Volume 28, Number 12, 2006 Probiotics for maintenance of remission in Crohn’s disease Implications for practice There is no evidence that probiotic preparations are superior to placebo or aminosalicylates for the maintenance of remission in patients with Crohn’s disease . It should be noted that aminosalicylates are probably not effective for maintenance of remission in Crohn’s disease (Akobeng 2005). The use of probiotics as maintenance therapy for medically or surgically induced remission in Crohn’s disease cannot be recommended at this time. Rolfe VE, Fortun PJ,Hawkey CJ, Bath-Hextall FJ. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2006, Issue 4. Probiotics for maintenance of remission in Crohn’s disease Implications for research Some probiotic agents may warrant further study. The limitations of small-scale studies should be taken into account, and larger scale studies are currently underway in Europe and the US. Better designed studies of probiotic treatment (dosage, duration and species) are required to determine the role of probiotics in CD treatment. Future trials should ensure consistent reporting of safety results, the dosage of probiotic(s) administered and levels of prebiotics and probiotics in the diet of the patient. Studies should evaluate the viability of live probiotic preparations, and gain an understanding of the levels already within the gastrointestinal tract prior to the start of the trial. Rolfe VE, Fortun PJ,Hawkey CJ, Bath-Hextall FJ. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2006, Issue 4. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review) Implications for practice It appears that ondansetron may reduce the amount of acute vomiting as well as reducing the number of children who required intravenous rehydration, and admission for acute gastroenteritis. However this conclusion is only based on four studies. In addition, participants in the ondansetron group did have more diarrhoea than in the placebo group, but the amount is likely not clinically significant. Alhashimi D, Al-Hashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database of Systematic Reviews 2009, Issue 2. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review) Implications for practice The four included trials reported on two possible routes of administration for two antiemetics; either oral or intravenous ondansetron or intravenous metoclopramide. It is conceivable that in the presence of persistent vomiting the intravenous single dose of ondansetron, if available,may offer some advantages over the oral route particularly in that the intravenous route is most likely to obviate any further irritation to the gastric mucosa. Alhashimi D, Al-Hashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database of Systematic Reviews 2009, Issue 2. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review) Implications for research In view of the likelihood of a higher incidence of gastroenteritis in developing countries the importance of further research into the effectiveness and cost effectiveness of antiemetics cannot be underestimated, particularly if this may lead to a reduction in the frequency with which costly intravenous fluids and hospitalisation are required. Alhashimi D, Al-Hashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database of Systematic Reviews 2009, Issue 2. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review) Implications for research Future research should also focus on outcomes that are of relevance to patients and thus the time to cessation of vomiting rather than a reduction in the number of episodes of vomiting as outcomes would appear to be more appropriate. Alhashimi D, Al-Hashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database of Systematic Reviews 2009, Issue 2. Classification of Laxative and Antidiarrheal Agentsileus: time to first bowel movement Site: http://www.numarklabs.com/images/evalable1.jpg Molecular structure of domperidone Savio C. Reddymasu, M.D., Irfan Soykan, M.D., and Richard W. McCallum, M.D.. Domperidone: Review of Pharmacology and Clinical Applications in Gastroenterology. Am J Gastroenterol 2007;102:2036–2045 Mechanisms of action of domperidone Savio C. Reddymasu, M.D., Irfan Soykan, M.D., and Richard W. McCallum, M.D.. Domperidone: Review of Pharmacology and Clinical Applications in Gastroenterology. Am J Gastroenterol 2007;102:2036–2045 Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials Six studies were included (total n = 707 patients). The combined results, analyzed with a per-protocol method that reported on the incidence of diarrhea during antibiotic treatment, showed significant benefit for the use of probiotics over placebo (relative risk [RR] 0.43, 95% confidence interval [CI] 0.25–0.75, I2 = 70.1%). In contrast, results from intention-to-treat analysis were nonsignificant overall (RR 1.01, 95% CI 0.64–1.61). Bradley C. Johnston, Alison L. Supina, Sunita Vohra. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. CMAJ • August 15, 2006 • 175(4) | 377. Probiotics for pediatric antibiotic-associated diarrhea: a metaanalysis of randomized placebo-controlled trials Subgroup analysis on 4 studies that provided at least 5 billion singlestrain colony-forming units (CFUs) daily (range 5.5–40 × 109 Lactobacillus GG, L. sporogens or Saccharomyces boulardii ) showed strong evidence with narrow CIs for the preventative effects of probiotics for antibiotic-associated diarrhea (RR 0.36, 95% CI 0.25–0.53, I2 = 3.5%). No serious adverse events were reported. Bradley C. Johnston, Alison L. Supina, Sunita Vohra. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. CMAJ • August 15, 2006 • 175(4) | 377. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials Interpretation: The potential protective effects of probiotics to prevent antibiotic-associated diarrhea in children do not withstand intention-to-treat analysis. Before routine use is recommended, further studies (with limited losses of subjects to follow-up) are merited. Trials should involve those probiotic strains and doses with the most promising evidence (i.e., Lactobacillus GG, L. sporogens or S. boulardii at 5–40 × 109 CFUs daily). Bradley C. Johnston, Alison L. Supina, Sunita Vohra. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. CMAJ • August 15, 2006 • 175(4) | 377. Model for antidiarrheal action of zinc in intestinal cells Angus G. Scrimgeoura and Henry C. Lukaskib. Zinc and diarrheal disease: current status and future perspectives. Curr Opin Clin Nutr Metab Care 11:711–717, 2008. Opioid Action in the Intestinal Tract Anthony De Luca*t and lan M. Coupart. Insights into Opioid Action in the Intestinal Tract. Pharmacol. Ther. Vol. 69, No. 2, pp. 103-115, 1996. Pathogenic mechanism of acute infectious diarrhoea R. Tormo, I. Polanco, E.Salazar-L, O. Goulet. Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril. Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 1008–1015. 2008. Mechanism of acute diarrhoeal illness caused by rotavirus R. Tormo, I. Polanco, E.Salazar-L, O. Goulet. Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril. Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 1008–1015. 2008. Mechanism of action of racecadotril R. Tormo, I. Polanco, E.Salazar-L, O. Goulet. Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril. Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 1008–1015. 2008. CFTR activators and inhibitors Jay R Thiagarajah and AS Verkman. CFTR pharmacology and its role in intestinal fluid secretion. Current Opinion in Pharmacology 2003, 3:594–599. Identification of CFTR inhibitors by high-throughput screening Jay R Thiagarajah and AS Verkman. CFTR pharmacology and its role in intestinal fluid secretion. Current Opinion in Pharmacology 2003, 3:594–599. Intestinal secretory pathways Jay R Thiagarajah and AS Verkman. CFTR pharmacology and its role in intestinal fluid secretion. Current Opinion in Pharmacology 2003, 3:594–599. Antidiarrheal properties of a CFTR inhibitor Jay R Thiagarajah and AS Verkman. CFTR pharmacology and its role in intestinal fluid secretion. Current Opinion in Pharmacology 2003, 3:594–599. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Approved and investigational agents for the treatment of IBS Michael J. Callahan. Irritable Bowel Syndrome Neuropharmacology. A Review of Approved and Investigational Compounds. J Clin Gn.\r~oerire,v/ 2002:35(Suppl.):S58-S67. Structure of ADL 8-2698 (+)-[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]-methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate. William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Whole-body autoradiographs (rat) with [14C]ADL 8-2698 William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Early clinical study William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 prevents morphine delay in oral-cecal transit time William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 does not reverse morphine analgesia William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 clinical benefits in opioid bowel dysfunction William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 in long-term opioid-treated patients: time to first bowel movement response William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Overall satisfaction with bowel movement William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 clinical benefits in 4-day progressive dose study William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 clinical benefits in postoperative ileus William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Postoperative ileus: time to first bowel movement William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Postoperative ileus: time to tolerability of solid food William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. Postoperative ileus: time to actual hospital discharge William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S. ADL 8-2698 reduced nausea and vomiting in postoperative ileus William K. Schmidt, Ph.D. . Alvimopan (ADL 8-2698) Is a Novel Peripheral Opioid Antagonist. The American Journal of Surgery 182 (Suppl to November 2001) 27S–38S.