Effects of age and disease on the pharmacokinetics and pharmacodynamics of sulindac.

The disposition and effect on hemostasis of a single 150 mg dose of sulindac was studied in young healthy subjects and in older patients with arthritis. Older patients were restudied after 2 weeks of sulindac, 150 mg b.i.d. The only difference in disposition of the first dose was a reduced plasma sulfone metabolite concentration in the elderly patients with arthritis. Chronic sulindac dosing resulted in accumulation of the drug and its sulfone and sulfide metabolites in plasma to a greater extent than previously reported for young subjects. No differences in renal clearance of sulindac and its sulfone metabolite related to age or chronic drug dosing were observed. No renal excretion of the active sulfide metabolite was detected. Bleeding time in the elderly patients was shorter than in the young healthy subjects before sulindac dosing, but was prolonged in the elderly patients after 2 weeks of dosing to values similar to control data from the young healthy subjects. This change correlated weakly with plasma sulfide metabolite concentrations. Differences in bleeding time were not reflected in changes in platelet aggregation induced by adenosine diphosphate either with respect to age or chronic drug dosing. Our data provide no justification for lowering the recommended dose of sulindac for patients older than 65 years of age.

A comparison of low-dose maintenance treatment with enprostil against ranitidine in the prevention of duodenal ulcer recurrence.

Enprostil, a prostaglandin E2 analogue, is effective in healing acute duodenal ulcer but its value in preventing recurrence, when given daily for maintenance therapy, is uncertain. In this three-centre study we compared enprostil and ranitidine maintenance therapy; the latter is known to reduce duodenal ulcer relapse rates. Patients whose duodenal ulcers had been healed by treatment with an H2-receptor antagonist were randomized to receive single-blind treatment with either 35 micrograms enprostil (n = 64) or 150 mg ranitidine (n = 64) at bedtime for periods of up to 1 year. Endoscopy was routinely performed at 3 months at one centre, and at 6 and 12 months at all three centres, or whenever ulcer symptoms recurred. Clinical assessment and laboratory investigations were performed every 3 months. Relapse, defined as recurrent ulcer with or without pain, or erosions with pain, was significantly greater in patients on enprostil, the comparative rates at 3, 6 and 12 months were: enprostil 23, 31 and 36% ranitidine 6, 12 and 17% (P = 0.013; P = 0.03 and P = 0.03, respectively). Thirty-one patients reported adverse events, the most common being headache (enprostil = 6, ranitidine = 2) and mild diarrhoea (enprostil = 6, ranitidine = 0). Four patients on enprostil were withdrawn for adverse events, although none terminated because of diarrhoea. There were no clinically significant changes in haematology or biochemistry. Enprostil may reduce duodenal ulcer relapse but at a dose of 35 micrograms nightly, it is less effective than 150 mg ranitidine nightly.

[1-14C]Ethanol breath test in alcoholic liver disease.

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.

Linking budgets to desired academic outputs at Dalhousie University.

In 1993, faced with continuing university budget reductions and dissatisfaction with the budget-allocation process, the Faculty of Medicine at Dalhousie University undertook a financial planning process. The goal was to develop a new resource-allocation model to better link academic budget support to desired academic outputs over a three-year period. Department heads categorized academic outputs (e.g., teaching, research, administration, and subcategories of these), determined their relative values (expressed as percentages of the total department budget to be projected), and identified acceptable units of measuring the outputs (e.g., for teaching in the first and second years of medical school, the unit was the number of teaching hours). When dollar values were assigned to the units of measure, the new model was used to calculate budget allocations for all departments. However, many departments showed large negative shifts in their budgets; these shifts were too large to be achieved within three years because of departments' contractual obligations. Therefore, a practical limit in budget shift was determined. This adjustment permitted a three-year projection of academic budgets to be made for each department. The use of the resource-allocation model has achieved the Faculty's goal by creating a better rationalization of budgets to academic outputs, but carries the risk that departments might abandon essential but "undervalued" academic activities.

The indications for and results of liver transplantation.

The overall indications for liver transplantations are becoming clearer. Patients with decompensated cirrhosis are poor risks and grafting should be done earlier. Results of transplants for primary biliary cirrhosis and well compensated cirrhosis are more encouraging. Transplantations for hepatocellular carcinoma is faced with the problem of high recurrences postoperatively. The presence of hepatitis B in a recipient is no longer a contraindication to grafting since this can be adequately treated with specific immunoglobulin. The latest introduction of Cyclosporin as an immunosuppressant may be of real benefit in liver transplantations.

The value of sputum cytology.

OBJECTIVE: To assess the value of cytologic examination of expectorated sputum in the diagnosis and management of patients with suspected lung cancer. DESIGN: Retrospective chart review. SETTING: Inpatient wards, tertiary care university hospital. MEASUREMENTS AND MAIN RESULTS: The charts of 357 patients were reviewed. Two hundred eighty-eight of the 357 patients had had initial sputum cytologic examination prior to other diagnostic procedures, of which 41 (15%) had positive cytologic results. Thirty-six of the 41 were confirmed histologically or shown to have metastatic spread by noninvasive tests. Of the 222 patients with negative or unsatisfactory sputum tests, 97 went on to bronchoscopy and 35 had needle-aspiration biopsies. In the population of patients whose chest x-rays were highly suggestive of primary or metastatic lung cancer, the positive rate for cytologic examination was 38/94 (40%). There was no false-positive test in this study. Of the 50 patients with positive cytologic results, five (10%) had diseases that were of a different cell type; two of these five (40%) had diseases that involved small-cell cancer. There was an unsatisfactory delay in obtaining these samples for analysis. CONCLUSIONS: Sputum cytology was found to be too insensitive and insufficiently accurate to be included in the routine workup of a patient suspected of having lung cancer. The results of the test did not influence further diagnostic procedures. This test should, therefore, be reserved for patients considered on initial assessment to be too sick for further investigations and treatment.

Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience.

Three hundred ninety-one cases of chronic lymphocytic leukemia (CLL) from the Tumour Registry of Manitoba, spanning a 20-year period from January 1960 to December 1979, were reviewed. Survival curves were developed using the staging systems of Rai and Binet. A clear separation in survival was found utilizing the system of Binet. Also, there was a significant increase in the development of secondary malignancies (observed, 53; expected, 31, p less than 0.01). However, there was no significant increase in secondary malignancies if only those malignancies occurring at least six months after the diagnosis of chronic lymphocytic leukemia was made were analyzed (observed, 38; expected, 29, p = 0.26). This suggests that the increase in secondary malignancies is not treatment-related, and may be due to the underlying disease.

A controlled clinical trial of cimetidine in the recurrence of variceal hemorrhage: implications about the pathogenesis of hemorrhage.

In a prospective randomized double-blind controlled trial, 51 patients, 16 with cirrhosis and 35 with extrahepatic portal hypertension all of whom presented with variceal bleeding, were given either long-term cimetidine in a dosage of 1.6 gm daily (24 patients) or placebo tablets (27 patients). Thirty-eight patients completed 2 years of treatment. For 16 patients with cirrhosis, there was no significant difference in the frequency of rebleeding between the cimetidine (62.5%) and placebo (75.0%) groups. Similarly, in 35 patients with extrahepatic portal hypertension, the frequency with which bleeding recurred in the cimetidine (37.5%) and placebo groups (36.8%) was not significantly different. Gastric acid and esophageal function studies, including basal acid output, lower esophageal sphincter pressure, esophageal acid reflux, and clearance measurements, showed no significant differences between patients with cirrhosis or extrahepatic portal hypertension both before and after variceal bleeding and in healthy control subjects. These results suggest that it is unlikely that gastric acid reflux is a significant factor in the pathogenesis of variceal hemorrhage, and cimetidine does not prevent recurrent episodes of bleeding.

Juvenile Sandhoff disease: some properties of the residual hexosaminidase in cultured fibroblasts.

The residual hexosaminidase isoenzymes in juvenile Sandhoff and infantile Sandhoff disease fibroblasts, have been determined by starch gel electrophoresis and column isoelectric focusing. Hex A and hex S are the major residual isozymes in fibroblasts from the juvenile patient, while hex B is barely detectable. Only hex S could be detected in fibroblasts from infantile Sandhoff patients. These results suggest that the defects in juvenile and infantile Sandhoff disease may be different allelic modifications of the beta subunit common to hex A and hex B.

Liver biopsy as a day-case procedure: selection and complications in 200 consecutive patients.

The selection of 200 consecutive patients who underwent liver biopsy as a day-case procedure and subsequent complications were reviewed, In 59 patients a diagnosis of cirrhosis was confirmed by histological examination. Six patients developed minor complications attributable to the procedure and had to stay longer in hospital, and another returned with abdominal pain the evening after the biopsy. With careful selection of patients, liver biopsy may be safely undertaken on a day-case basis.

Second malignancies in non-Hodgkin's lymphoma.

Six hundred thirty cases of non-Hodgkin's lymphoma (NHL) in the Tumour Registry of Manitoba spanning an 11-year period from January 1968 to December 1978 were reviewed. There were 34 cancers from 31 individuals who developed the cancer at least six months after diagnosis of NHL. There was no statistical difference in the incidence of second malignancies in this disease compared with an age-matched population in Manitoba. In particular, no cases of acute leukemia were identified.

Improved survival following injection sclerotherapy for esophageal varices: final analysis of a controlled trial.

Long-term follow-up (median: 37 months; range: 19 to 68) of the 116 patients (56 sclerotherapy, 60 control group) entered into a controlled trial of endoscopic variceal sclerotherapy has shown a total of 18 deaths in the sclerotherapy group, including five from variceal bleeding compared with 32 deaths in the control group (p less than 0.01), of which 25 were from variceal hemorrhage (p less than 0.001). Survival as assessed by cumulative life analysis was significantly better in those treated by sclerotherapy (p less than 0.001). Both the cumulative proportion of patients rebleeding and the total number of episodes of variceal hemorrhage were also significantly less in the sclerotherapy group (p less than 0.01). Recurrence of varices was observed in 27 of 45 patients in whom variceal obliteration was initially observed at a median of 11 months (range: 2 to 27) later, although in only 12 of these did bleeding recur and was the cause of death in one.

H2-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Two controlled trials.

In two controlled trials, involving 75 patients, on the prevention of bleeding from gastric erosions in fulminant hepatic failure, antacids given four-hourly had no significant effect. Only 35% of intragastric pH recordings taken at two-hourly intervals in the treated group were maintained above 5 with the doses used, whereas this could be consistently achieved with the histamine H2-receptor antagonists, metiamide and cimetidine. In the group receiving these drugs only 1 patient out of 26 bled, compared with 13 (54%) of the controls, a highly significant difference. Blood-transfusion requirements were significantly less in those treated with H2-receptor antagonists.

Eosinophilic fasciitis in a pair of siblings.

Two siblings, a 38-year-old woman and a 33-year-old man, developed eosinophilic fasciitis within a period of 6 months. They were found to have identical HLA-A, B, DR, and DQ antigens, raising the possibility of a genetic influence in the development of this disease. No common environmental factors close to the time of onset were identified; however, the possibility of a common, remote environmental factor cannot be discounted.

Injection sclerotherapy for oesophageal varices: a prospective randomised trial of different treatment schedules.

A prospective randomised study to compare the efficacy and complications of injection sclerotherapy carried out at intervals of one week and three weeks up to the time obliteration of varices was achieved, was undertaken in 55 patients (48 cirrhosis, six portal vein thrombosis, one nodular regenerative hyperplasia). The number of courses of injection required for obliteration of the varices was not different in the two groups and despite a shorter time scale for obliteration in the weekly treated patients the frequency with which further episodes of bleeding occurred before that was not significantly less. Mucosal ulceration during the period required for obliteration was observed at endoscopy more frequently in the weekly treated patients but was not associated with a greater frequency of postinjection pain, dysphagia or of long term stricture formation.

A prospective reappraisal of emergency endoscopy in patients with portal hypertension.

In a prospective study of emergency endoscopy in patients with portal hypertension and oesophageal varices referred to King's College Hospital with acute upper gastrointestinal bleeding, initial endoscopic examination on 90 separate consecutive hospital admissions carried out within 24 h of clinical haemorrhage showed active variceal bleeding in only 21 (23.3%) cases. Coexisting upper gastrointestinal lesions were present in 38.8% of examinations, but active bleeding from these sites was seen in only five cases (5.6%). Of the 64 cases in which no active bleeding was seen at initial endoscopy, 39 (60.9%) rebled during that admission, and repeat endoscopy in 27 of these, carried out within 1 h of this episode, revealed active variceal haemorrhage in 20 (74.1%) cases. These results indicate that variceal haemorrhage is intermittent, and, although bleeding may often stop spontaneously, a high proportion of patients subsequently rebleed, and this is invariably from varices rather than from coexisting upper gastrointestinal lesions. In addition, these findings confirm the importance of emergency endoscopy in making the correct decision about acute management.

Recurrence of primary biliary cirrhosis after liver transplantation.

Three patients who had undergone orthrotopic liver transplantation for primary biliary cirrhosis and were being maintained on immunosuppressive therapy were investigated 31/2 to 41/2 years later because of the redevelopment of pruritus and mild jaundice. In one patient pigmentation was again evident, and all three had a rise in the titer of serum mitochondrial antibody after an initial fall. Liver histology showed features of primary biliary cirrhosis with non-suppurative destructive cholangitis, lymphoid aggregates, and increased deposition of copper-binding protein in the absence of cholestasis. None of these features was found in patients who had received grafts for other conditions and had lived for comparable periods, nor were they found in patients who had had rejection with bile-duct abnormalities. The overall findings indicate a recurrence of primary biliary cirrhosis in the donor organ.