Misoprostol in the treatment of duodenal ulcer refractory to H2-blocker therapy. A placebo-controlled, multicenter, double-blind, randomized trial.

A multicenter, double-blind, randomized study compared 200 micrograms of misoprostol and placebo four times daily for four weeks in the treatment of 225 patients with duodenal ulcer (0.7 cm to 2.0 cm in size) persisting after at least four weeks of adequate, conventional therapy with cimetidine or ranitidine. Misoprostol was significantly superior to placebo in healing duodenal ulcers (achieving a healing rate of 37 percent versus 22 percent in the placebo group [p = 0.02], and in relieving ulcer pain [p = 0.01]). Healing also occurred more frequently with misoprostol than with placebo in patients with subgroups of particularly resistant ulcers. In the treatment of ulcers refractory to at least eight weeks of histamine H2-blocker therapy, misoprostol achieved a healing rate of 42 percent versus 20 percent with placebo. In the treatment of pyloric channel ulcers, 28 percent of patients in the misoprostol group showed healing as compared with 20 percent in the placebo group. Diarrhea was reported by 15.4 percent and 3.4 percent of patients receiving misoprostol and placebo, respectively, and was usually mild and transient. Misoprostol is safe and effective therapy for duodenal ulcers that have not healed during the course of H2-blocker therapy.

The relationship between plasma cortisol and gastric mucosa prostaglandin levels in rats with stress ulcers.

A correlation between the levels of plasma cortisol, gastric mucosal prostaglandins and the degree of gastric ulceration produced by stress in rats was examined. Four groups of rats were evaluated. Group A, the cold stressed group; group B, their controls; group C, those receiving intraperitoneal indomethacin; and group D, those receiving intraperitoneal saline. Group A developed stress ulcers and their gastric mucosal prostaglandin levels (prostaglandin E2 (PGE2) and prostacyclin levels, as measured by its stable metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF-1 alpha, but not thromboxane) were significantly reduced when compared with their respective non-stressed controls. The plasma cortisol levels in both group A and B increased slightly in the first hour but there was no statistical difference between the two groups and there was no change at 2, 3 or 4 h of stress. Group C (indomethacin) also developed ulcers and had low gastric mucosal prostaglandin levels when compared with group D (saline). The plasma cortisol levels did not alter in either group C or D. It has been postulated that stress ulcers may involve the depletion of gastric mucosal prostaglandin levels which, in turn, may be a consequence of a higher plasma cortisol level. A decrease in gastric prostaglandins independent of any change of plasma cortisol levels was demonstrated in this study and the mechanism of production of stress gastric ulcers remains obscure.

Liver function in postmenopausal women on estrogen-androgen hormone replacement therapy: a meta-analysis of eight clinical trials.

OBJECTIVE: To compare hepatic biochemical changes of a combined estrogen-androgen preparation with that of estrogen alone in postmenopausal women. DESIGN: Hepatic biochemical values from 511 surgical and 130 nonsurgically menopausal women being treated with hormone replacement therapy were pooled from eight similarly designed studies performed between March 1988 and January 1996 comparing esterified estrogen-methyl-testosterone preparations with esterified estrogen, conjugated equine estrogens, and placebo controls. The eight studies in this meta-analysis were controlled, randomized, multicenter, double-blind with identical or similar treatment arms. For hepatic biochemistry parameters, raw data summaries and mean changes from baseline values with standard error (SE) were evaluated for the dosages and treatment groups at various time periods throughout the studies. RESULTS: Eight controlled trials involving 641 surgically and nonsurgically menopausal women were included. Changes from the pretreatment baseline values of liver function were compared at 1, 3, 6, 12, 18, and 24 months of therapy. No patients demonstrated hepatotoxicity or clinically significant elevation of liver biochemistry values. None of the liver biochemistry changes measured in these studies were of clinical significance, nor were there biochemical differences between estrogen therapy alone compared with combined esterified estrogen-methyltestosterone preparation when administered to postmenopausal women during a period of up to 24 months. CONCLUSIONS: Combined esterified estrogen-methyltestosterone therapy (in doses of 0.625 mg esterified estrogen + 1.25 mg methyltestosterone or 1.25 mg esterified estrogen + 2.5 mg methyltestosterone) was found to be safe regarding hepatic function in postmenopausal women during the course of 24 months in eight controlled clinical trials.

Liver dysfunction in ovarian hyperstimulation syndrome. A case report.

Ovarian hyperstimulation syndrome (OHS) is one of the potential complications associated with the use of human menopausal gonadotropin therapy. We recently dealt with a case of severe OHS presenting features of liver dysfunction; such a case has not been reported on before.

Clinical trial: interferon alpha-2b continuous long-term therapy vs. repeated 24-week cycles for re-treating chronic hepatitis C.

BACKGROUND: Treatment options are limited for patients with hepatitis C virus who do not experience sustained viral eradication with pegylated interferon and ribavirin therapy. AIM: To compare, in an open-label, randomized study, long-term continuous interferon alpha-2b treatment with repeated 24-week courses in patients with chronic hepatitis C virus that relapsed after prior interferon monotherapy. METHODS: A total of 499 patients received 24 weeks of interferon alpha-2b, 3 MIU administered 3 TIW. Responders (normal alanine aminotransferase and negative hepatitis C virus -RNA, n = 244) were then randomized to continuous interferon therapy (1, 2 or 3 MIU TIW depending on response) or cyclical therapy (3 MIU TIW for 24 weeks per relapse). Mean Knodell inflammation (I + II + III) and necrosis (IV) scores at baseline vs. year 2 were compared. RESULTS: Patients receiving continuous low-dose therapy vs. cycled therapy had larger reductions in inflammation (-3.9 vs. -3.1) and fibrosis (-0.49 vs. -0.24). Among both groups, the mean change was -3.4 for inflammation and -0.36 for fibrosis. Overall, 73% (95% CI: 67-79) of patients experienced reduced inflammation and 28% (95% CI: 22-34) had reduced fibrosis. CONCLUSIONS: Our results suggest hepatitis C virus patients experiencing viral suppression during long-term maintenance therapy with interferon demonstrate histological improvement. Further prospective trials testing this hypothesis are in progress.

Salicylate hepatotoxicity: the potential role of hypoalbuminemia.

Seventeen patients suffering from an initial attack of acute rheumatic fever were studied during treatment with phenoxymethyl penicillin and salicylates (600 mg orally every 4 or 6 hours). Elevated transaminase (SGOT) levels occurred in nine patients. The SGOT levels were directly related to serum salicylate levels (r = 0.668) and inversely to the serum albumin level (r = -0.418). SGOT response was greater in patients with a serum albumin of less than 3.5 g/dl (P < 0.001). In hypoalbuminemia, the ratio of free salicylate to bound salicylate rises and the free salicylate might be more active and thus more hepatotoxic even at relatively low total serum salicylate levels. In all patients with hypoalbuminemia of less than 3.5 g/dl, close monitoring the SGOT is advisable, especially if the level of total serum salicylate is 15 mg/dl or higher.

The serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase ratio as a prognostic index in severe acute viral hepatitis.

The SGOT/SGPT ratio was studied in 25 patients with severe acute viral hepatitis due to either B or non A-non B hepatitis. The transaminase levels were performed within 10 days of onset of the hepatitis or within 4 days of the diagnosis of fulminant hepatic failure. Twelve patients died of their acute illness. There was a significant difference between the SGOT/SGPT ratios of females who died mean = 2.05) and lived (mean 0.45) (p less than 0.001) and between the SGOT/SGPT ratios of males who died (mean - 1.01) and lived (mean 0.45) (p less than 0.02). Using 95% confidence intervals the expected ratios for combined sexes were calculated to be 0.31 to 0.63 for survivors and from 1.20 to 2.26 for nonsurvivors. Neither age not viral etiology affected the prognosis in this study.

Hepatitis B: diagnosis, prevention, and treatment.

Hepatitis B virus (HBV) infection occurs worldwide and is an important cause of acute and chronic viral hepatitis in the US. In this review, I describe the virus, risk factors for infection, clinical features of infection, results of laboratory tests during infection, and standard and emerging treatment for chronic infection. Although 95% of adult patients recover completely from HBV infection, 90% of children < or = 4 years of age develop chronic infection. Active vaccination is highly efficacious.

The anti-arrhythmic effects of perhexiline maleate in patients with ischaemic heart disease.

In a preliminary study which lasted 14 weeks, an anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dosage of 200 mg twice a day to 7 patients who were suffering from cardiac arrhythmias associated with ischaemic heart disease. There was a significant reduction in ventricular extrasystoles during the 4th and 8th weeks of the study in 6 of the patients who had multiple ventricular ectopic beats. In 4 of these patients, an effective anti-arrhythmic response was maintained until the end of the study. These findings confirm other studies regarding the efficacy of the preparation in reducing ventricular extrasystoles in patients with cardiac ischaemia.

The clinical presentation of Gilbert's disease in 26 patients.

Twenty-six patients with Gilbert's disease (congenital, non-haemolytic unconjugated hyperbilirubinaemia) were analysed regarding their clinical presentation, age at onset of symptoms, sex, frequency of symptoms, family history, race and religion. Seventy-three per cent were men, the mean age at onset of symptoms was 21 years, and frequency of symptoms ranged from 4 times a year to once every 5 years. The symptoms, which were extremely vague, included the following: recurrent asymptomatic jaundice in 74%, malaise in 66%, asthenia in 65%, and vague abdominal distension in 52% of patients. Eight per cent of patients were totally asymptomatic. There did not appear to be any particular race or religious group with a higher incidence of the disorder. No abnormal clinical features apart from mild jaundice were detected. The entirely benign nature of the syndrome is stressed, and a normal life expectancy is the rule. The avoidance of prolonged fasting is the best therapeutic measure, although enzyme induction by phenobarbitone therapy may have some place in the management of symptoms.

Raised serum transaminase levels in patients with rheumatic fever treated with salicylates.

Of 11 patients with acute rheumatic fever, 9 were treated with a total daily salicylate dosage of 3,6 g or less, 1 patient required a total daily dosage of 5,4 g and another required 9,0 g daily. Six of the 11 patients had elevated serum transaminase levels, and all were asymptomatic. The elevated transaminase levels appear to bear a direct relationship to the serum salicylate level, and a serum salicylate level of 19,2 mg/100 ml appears to be the critical point. In 5 out of the 6 patients with elevated transaminases, the serum salicylate level exceeded 19,2 mg/100 ml, while in the 5 patients with normal transaminases the serum salicylate level did not exceed 19,2 mg/100 ml. Also, in 10 of the 11 patients eosinophilia was noted, but this decreased despite continued or increased salicylate administration. A narrow margin thus appears to exist between therapeutic serum salicylate levels and hepatotoxic levels, and serial serum transaminase estimations are advocated in patients on long-term salicylate therapy.

Severe recurrent hepatic encephalopathy that responded to oral branched chain amino acids.

Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with acute or chronic liver disease. Its pathogenesis remains unclear; however, it appears to be multifactorial. There are several conventional treatments for this condition, such as lactulose, neomycin, and protein restriction. There is significant controversy regarding the role of branched chain amino acids in the treatment of chronic hepatic encephalopathy. We describe a patient who had hepatic encephalopathy secondary to Budd-Chairi syndrome and a mesoatrial shunt that failed vigorous conventional therapy. She required multiple hospitalizations for severe recurrent encephalopathy. The patient was considered for a colonic exclusion procedure for the management of intractable encephalopathy. However, branched amino acid therapy was instituted as a last measure before the contemplated surgery, and the patient's encephalopathy responded in dramatic fashion, and she remained free from encephalopathy during a prolonged follow-up.

Ischemic hepatitis: widening horizons.

Ischemic hepatitis is not an uncommon complication of reversible severe hypotension or cardiac failure. The prognosis usually is determined by the cause of the initial hypotension or cardiac failure, rather than the subsequent hepatic dysfunction. We report a retrospective analysis of nine patients with ischemic hepatitis in which previously unreported clinical and biochemical abnormalities are noted. The clinical and biochemical course of the patients were reviewed until recovery or death from ischemic hepatitis. All the patients had a rapid striking elevation of aspartate aminotransferase, and lactic dehydrogenase, with an equally rapid resolution of these parameters. Abnormal serum glucose levels occurred in six patients (none of whom had a prior carbohydrate intolerance). Insulin therapy was given to three patients for a limited period. Renal impairment was manifest in all nine patients, and it resolved spontaneously within 10 days. Altered mental status was detected in six patients; the changes reverted to normal within 7 days of their onset. A preexisting anemia (hemoglobin less than 11.0 g/dl) was noted on admission in four patients, and it did not appear to potentiate the manifestations of the hepatic ischemia. We conclude that ischemic hepatitis should be anticipated in all patients with a recent history of systemic hypotension. It should be considered in the differential diagnosis of patients with unexplained hepatitis; the early massive rise in lactic dehydrogenase, the rapid fall in transaminases, and the early mild/moderate renal failure strongly suggest ischemic hepatitis. Patients with ischemic hepatitis can manifest reversible renal failure, mental confusion, and hyperglycemia which may require insulin for its control.

Spontaneous rupture of a bile duct and its endoscopic management in a patient with Caroli's syndrome.

Caroli's syndrome is a condition of cystic dilation of intrahepatic bile ducts that communicate with the extrahepatic biliary tree. Patients with Caroli's syndrome are prone to develop several complications. These include bacterial cholangitis, biliary sludge, calculi, and cholangiocarcinoma. We describe an adult patient with Caroli's syndrome in whom spontaneous rupture of a bile duct developed with consequent biliary peritonitis, which was successfully managed with endoscopic stent placement.

The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, non-shunted patients with cirrhosis.

Thirty-seven patients, all with histologic evidence of cirrhosis and with a normal neurological examination and normal mental status were evaluated by psychometric testing for subclinical hepatic encephalopathy. They were all regarded as having well compensated cirrhosis, not requiring any treatment or dietary restrictions and they were working, and many of them driving. A group of 19 patients with a history of alcoholism, or medical disorders, but without clinical or biochemical evidence of cirrhosis, served as controls. They were matched by age, sex, education, and alcohol consumption. Investigations performed were an EEG, fasting arterial ammonia, liver biochemical tests and a series of verbal and performance psychometric tests. The EEG was abnormal in 3 (8.3%) of patients, the ammonia elevated in 17 (45.9%) of patients and 26 patients (70.3%) failed 2 or more psychometric tests, as compared to 2 (10.5%) of the control group. It is concluded that 2 out of 3 patients with stable, well compensated cirrhosis were suffering from subclinical hepatic encephalopathy and that impairment of performance rather than verbal skills occurred. The digital symbol test, trail test (number connection test) and block design tests readily identified the patients with subclinical hepatic encephalopathy. The implication of these observations in patients with cirrhosis, especially those working in mechanical or skilled occupations, needs consideration.

The pH of ascitic fluid in the diagnosis of spontaneous bacterial peritonitis in alcoholic cirrhosis.

Fifty-six patients with alcoholic cirrhosis and ascites were studied. The ascitic fluid was analyzed for pH, PO2, PCO2 glucose, protein, specific gravity, amylase, lactic dehydrogenase, white blood cell count, polymorphonuclear count, and cytology. It was also cultured aerobically and anaerobically. Simultaneously, arterial blood was analyzed for pH, PO2, and PCO2. Venous blood was analyzed for complete blood count, protein, aspartate transaminase, and it was also cultured under aerobic and anaerobic conditions. Six patients had spontaneous bacterial peritonitis (SBP), i.e., culture was positive for Escherichia coli in five and Streptococcus faecalis in one. The mean (+/- S.E.) ascitic fluid pH in the SBP group wa 7.25 +/- 0.06 with a range of 7.12 to 7.31, while the ascitic fluid pH in the group with sterile ascites was 7.47 +/- 0.07 with a range of 7.39 to 7.58. The pH of the blood in both groups was 7.47 +/- 0.03. The pH of the ascites in the SBP group was significantly different from the pH in the group with sterile ascites, p less than 0.001. It was also significantly different from the blood pH, p less than 0.001. Highly significant inverse correlations existed between the ascitic pH in the SBP group and the ascitic white blood cell count (r = 0.84, p less than 0.01) and between the ascite pH in the SBP group and the ascitic polymorphonuclear count (r = -0.87 ,p less than 0.01). The ascitic fluid pH is recommended as an easy, quick, sensitive, and specific means of diagnosing SBP and it overcomes the problem of the present SBP diagnostic methods of utilizing an absolute white blood cell count greater than 500 per mm3 or a polymorphonuclear count greater than 250 per mm3 in which false positive interpretations occur.

Cimetidine-induced hemolytic anemia: the fallacy of clinical associations.

Two patients developed hemolytic anemia while taking cimetidine. Neither patient was taking other drugs known to cause hemolytic anemia. In both, the hemolytic anemia resolved after the drug was stopped. In one patient, the direct antiglobulin (Coombs') test was strongly positive when the hemolytic anemia was recognized and became only weakly positive as the hemolysis subsided. However, serologic studies for antidrug antibodies yielded negative results in both patients; readministration of cimetidine for 55 days in patient 1 and for more than 24 months in patient 2 did not cause recurrence of hemolysis. We conclude that we cannot incriminate cimetidine as the cause of the hemolytic anemia in either of our patients. These findings emphasize that a temporal association of drug administration and hemolytic anemia is not proof of a cause-effect relationship and that reports of drug-related adverse hematologic effects must be interpreted with caution.

A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the treatment of active duodenal ulcer disease.

The efficacy and safety of famotidine, a potent new long-acting H2-receptor antagonist, was compared with placebo in a multicenter, double-blind, randomized, placebo-controlled study in the United States. A total of 384 patients with endoscopically proven acute duodenal ulcer disease were enrolled. Patients received either famotidine or a placebo. The patients receiving famotidine were treated with one of three dose regimens, 40 mg h.s., 40 mg b.i.d., or 20 mg b.i.d. Patients were reassessed by endoscopy at 2, 4, and 8 wk if ulcer healing had not occurred sooner. A diary was kept to record the duration and intensity of the day and night pain and the amount of Gelusil antacid (Parke-Davis, Morris Plains, N.J.) ingested. Three hundred sixty-three patients met the evaluation criteria. The results revealed a 4-wk healing rate of 70%, 75%, 67%, and 31% for the famotidine 40 mg h.s., 40 mg b.i.d., 20 mg b.i.d., and placebo groups, respectively. The 8-wk healing rates for the same respective groups were 83%, 82%, 82%, 45%. Ulcer pain and antacid consumption occurred less often in the famotidine groups. The clinical and laboratory safety profile of the famotidine groups was similar to that of the placebo group. Famotidine appears to be an effective and safe once-a-day therapy for the treatment of acute duodenal ulcer disease. The recommended dosage is 40 mg h.s.