Effect of cirrhosis and debrisoquin phenotype on the disposition and effects of pinacidil.

Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent. It is metabolized in humans to pinacidil N-oxide. To determine whether pinacidil's metabolism or effects were influenced by either liver disease or the subject's debrisoquin phenotype, eight patients with chronic stable cirrhosis and 13 healthy subjects were studied. Seven of the healthy volunteers were extensive metabolizers of debrisoquin, whereas six were of the poor metabolizer phenotype. Neither the clearance of pinacidil nor the production of the N-oxide was altered by the subjects' debrisoquin phenotype. Cirrhosis produced a 50% reduction in pinacidil's clearance (20.7 +/- 1.4 vs. 42.1 +/- 5.1 L/hr; P less than 0.0005) and a prolongation in the elimination t1/2 from 3.9 +/- 0.3 to 6.1 +/- 0.6 hours (P less than 0.01). Less pinacidil was metabolized to the N-oxide metabolite in the patients with cirrhosis than in the normal individuals. Thus pinacidil's metabolism and clearance are reduced in patients with cirrhosis but are independent of debrisoquin phenotype.

Encainide disposition in patients with chronic cirrhosis.

The antiarrhythmic agent encainide undergoes extensive first-pass hepatic metabolism after oral dosing. The active metabolites O-desmethylencainide and 3-methoxy-O-desmethylencainide are formed in subjects who are extensive metabolizers (EMs), a phenotypic trait that cosegregates with that of debrisoquin. Because of the possibility that drug metabolism is altered by liver dysfunction, the disposition of encainide and its metabolites was studied in six such EMs with cirrhosis and compared with that in eight normal subjects of the same phenotype. Patients with cirrhosis had lower systemic and oral clearances of encainide, resulting in a threefold increase in oral bioavailability. The plasma concentration of encainide was significantly higher among the patients with cirrhosis, whereas the plasma levels of the respective metabolites were comparable with those in normal subjects, resulting in no change in the patient's ECG intervals. Encainide is, therefore, an example of a drug in which cirrhosis causes a three- to fourfold increase in parent drug concentrations. However, because no change occurs in the levels of the pharmacologically active metabolites, dosage adjustment is probably not required in patients with cirrhosis.

Herpes zoster of the larynx after intubational trauma.

Multiple or prolonged endotracheal intubations may result in laryngeal trauma. This case illustrates that recrudescence of latent varicella-zoster virus as herpes zoster of the larynx, with subsequent laryngeal paralysis, can complicate intubation. Consequently, physicians should strive to minimize laryngeal injury in this setting. It is advised that careful laryngeal examination follow extubation.

Primary sclerosing cholangitis associated with massive intraabdominal lymphadenopathy.

A 40-year-old man with a history of insulin-dependent diabetes mellitus was admitted to the hospital because of jaundice and pruritus. During his evaluation the diagnosis of primary sclerosing cholangitis and "microscopic" ulcerative colitis were established. Massive intraabdominal lymphadenopathy was discovered on CT scan and histological examination eventually proved this to be follicular hyperplasia. The case herein reported documents the association of primary sclerosing cholangitis with diabetes mellitus and ulcerative colitis as well as reporting the occurrence of massive intraabdominal lymphadenopathy.

The effect of cimetidine on hepatic drug elimination in cirrhosis.

Both cimetidine therapy and cirrhosis individually interfere with normal elimination of various drugs. Cimetidine is often prescribed in patients with cirrhosis but there is incomplete data on its effect on drug elimination in cirrhotics. The purpose of this study was to address this issue. Eight stable cirrhotics were studied prior to and following 7 days of cimetidine administration, (300 mg orally q.i.d.). Chlordiazepoxide (Librium), which is eliminated by the liver after demethylation, and indocyanine green, which is removed by the liver without biotransformation, were used as probes. Consistent with the concept that cimetidine interferes with drug metabolism by inhibiting microsomal oxidation, chlordiazepoxide clearance in the cirrhotics was inhibited by cimetidine (p less than 0.05), but indocyanine green clearance was unaffected. As shown by us previously (Roberts, R. K. et al., Gastroenterology 1978; 75:479-485), untreated cirrhotics had substantially lower chlordiazepoxide clearance than did controls. The inhibitory effect of cimetidine on chlordiazepoxide clearance was less in cirrhotics than in controls (p less than 0.05). In all subjects, there was excellent correlation between initial clearance and magnitude of depression in clearance after cimetidine, i.e., the larger the initial clearance, the larger the change (r = 0.97, p less than 0.0001). Forty-eight hours after stopping cimetidine, chlordiazepoxide clearance returned to baseline in cirrhotics and controls. Our data demonstrate that cimetidine and cirrhosis may act additively to impair drug metabolism. This effect of cimetidine on chlordiazepoxide clearance is smaller in cirrhotics than in controls, but, because of impaired initial drug elimination in cirrhosis, it may result in adverse clinical effects.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic, cholestatic disease affecting the biliary tree. Recent data suggest an autoimmune etiology. Clinical findings, roentgenographic characteristics, and compatible liver histology will help in establishing the diagnosis. There is no known treatment for cure, though relief of symptoms may be accomplished with certain drugs, such as antibiotics for cholangitis and cholestyramine for pruritus. Death usually ensues within five to seven years after diagnosis, as a consequence of liver failure, cholangitis, and cholangiocarcinoma.

Giant fibrovascular polyp of the esophagus.

An adult patient with a giant fibrovascular esophageal polyp, measuring 17 cm in length, is described in this report. The patient presented with dysphagia and intermittent partial regurgitation of a fleshy mass in the mouth, only after the polyp had attained giant proportions. The polyp appeared as a large polypoid filling defect on a barium swallow and the findings were confirmed at endoscopy. The stalk was attached just below the cricopharyngeus muscle, and the club-shaped polyp extended almost up to the gastroesophageal junction. Because of the vascularity of this large structure and the proximity of respiratory passages to the site of attachment of the stalk, surgical resection of the polyp was undertaken.

Endoscopic variceal sclerotherapy: experience with 30 patients.

Endoscopic sclerotherapy is used to obliterate esophageal varices in an attempt to decrease bleeding episodes. First reported in the 1940s, sclerotherapy has recently enjoyed renewed interest because surgical shunting procedures, though effective in preventing rebleeding, are associated with significant mortality and provide no increase in long-term survival. Sclerotherapy, using a flexible endoscope, has been used in 30 patients at Vanderbilt University and the VA Medical Center, Nashville, Tenn. We present our clinical experience, compare our results with those of other groups, and discuss other approaches to the management of bleeding varices.

Radiographic appearance of the nonabsorbed (unconjugated) and conjugated sodium tyropanoate (Bilopaque) in the bowel.

A series of abdominal radiographs were taken in eight normal volunteers after the ingestion of sodium tyropanoate (Bilopaque). These showed nonabsorbed sodium tyropanoate to have a granular appearance, while the conjugated form had a smooth homogeneous appearance. The appearance of conjugated sodium tyropanoate in the bowel has the same diagnostic significance as conjugated iopanoic acid in the presence of a nonvisualized gallbladder. It indicates that the contrast material has passed through the hepatic ductal system and that there has been an opportunity for the gallbladder to opacify.

Anaerobic bacterial populations on normal and diseased human biopsy tissue obtained at colonoscopy.

Human epithelium was cultured to characterize differences in microbial populations between regions of normal colon and between polyps, inflammatory bowel disease, and cancer and their respective adjacent normal mucosa. Twenty-one patients (12 polyps, 5 inflammatory bowel disease, 4 cancer) underwent colonoscopy with anaerobic culture of mucosal biopsies from normal and diseased ascending, transverse, descending, and sigmoid colon. No differences for total number of organisms and recovery of species between ascending colon and other normal regions were seen except for sigmoid colon. Significant differences between polyps and adjacent normal tissue were seen for total number of organisms and recovery of genera and species. No significant differences in total number of organisms and recovery of genera were seen between cancer and inflammatory bowel disease and their respective adjacent normal tissue. The recovery of genera from polyps and normal tissue was Bacteroides greater than Fusobacterium greater than Clostridium greater than Eubacterium greater than Peptostreptococcus. These data suggest that (i) the total number of anaerobic organisms and species remained relatively constant, except for lower numbers in normal distal colon which were probably a result of the preparation for colonoscopy; (ii) polyp formation favored increased microbial colonization; and (iii) the increased number of organisms generally reflected those genera and species seen on adjacent normal mucosa.

Inhibition of microsomal drug metabolism by histamine H2-receptor antagonists studied in vivo and in vitro in rodents.

Cimetidine has been demonstrated to impair microsomal oxidative drug metabolism in a dose-dependent manner in an animal model. The inhibition has also been shown to be rapid, occurring after a single dose. In the present study we demonstrate that recovery from inhibition after cimetidine withdrawal is also rapid, occurring within 24 h. Furthermore, chronic dosing with cimetidine does not result in tolerance to the inhibitory effect. Other H2-antihistamines have also been studied both in vivo and in vitro. Based on spectral binding changes, in vitro enzyme assays and in vivo aminopyrine breath tests, ICI 125,211, ranitidine, and cimetidine sulfoxide are much less inhibitory than cimetidine. The ability of cimetidine to impair the elimination of aminopyrine in the mouse after acute liver damage was greater than in the normal mouse.

Conjugated sodium tyropanoate (Bilopaque) in the bowel: significance of its presence or absence after first-dose oral cholecystography.

Oral cholecystography following the ingestion of 4.5 g of sodium tyropanoate (Bilopaque) was performed in 1,053 patients. The radiographs of 89 patients in whom the gallbladder was either faintly visualized or nonvisualized were reviewed for the presence of conjugated contrast material in the bowel. All 89 of these patients underwent second-dose cholecystography. Oral cholecystography was found to be 100% accurate in the diagnosis of gallbladder disease when conjugated contrast media was found in the bowel in the presence of a faintly visualized or nonvisualized gallbladder. When this combination of findings is seen on the first-dose examination, a second-dose examination is unnecessary. When no conjugated contrast material is seen in the bowel after a first dose, a second dose is helpful only in those patients with normal biochemical liver function tests.

In vitro antagonism of benzodiazepine binding to cerebral receptors by H1 and H2 antihistamines.

Antihistamines directed at either the H1 or H2 histamine receptor have the well-known side effect of sedation. The mechanism for the CNS depressant action of antihistamines is unknown. We examine here the possibility that the mechanism may involve modulation of the cerebral benzodiazepine receptor. We demonstrate that cimetidine and pyrilamine are competitive antagonists of 3H-benzodiazepine binding to human cerebral receptor in vitro. The inhibition of radioligand binding was not specific for benzodiazepine receptor, however, since antihistamines also antagonized binding to GABA, opiate, and muscarinic acetylcholine receptor. The interaction of antihistamine with CNS receptors other than histamine receptor may explain, at least in part, the side effect of sedation.

Infarction after embolization of the ileocolic artery.

Treatment of colonic hemorrhage by therapeutic embolization of the involved artery may, rarely, result in bowel infarction. In one patient with angiodysplasia, bowel infarction resulted from a therapeutic embolization of the ileocolic artery, because of the arterial anatomy of the cecum, occlusion of the cecal branches can result in devascularization of the cecum and appendix, even if the colic and ileal branches are not occluded. Thus, the ileocolic artery may not be a good candidate for therapeutic embolization.

Gastric varices secondary to splenic vein occlusion: radiographic diagnosis and clinical significance.

The radiographic appearance and clinical significance of gastric varices in the absence of esophageal varices and secondary to splenic vein occlusion were studied. Eighteen patients were evaluated through medical records, angiography, and barium studies of the stomach and esophagus. The presence of splenic vein occlusion was determined by arteriography in 18 patients and its etiology confirmed by surgery in 17 patients. This condition should be suspected in patients with chronic abdominal pain, weight loss, and iron deficiency anemia who show fundal polypoid filling defects or prominent gastric folds on an upper GI series.