Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection.

Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log(10). Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 microg/ml x hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

Delayed-onset ticlopidine-induced cholestatic jaundice.

An 86-year-old man experienced a rash approximately 2 weeks after starting ticlopidine therapy, necessitating discontinuation of the drug. About 1 month later, despite discontinuation, he developed jaundice and liver test abnormalities. These resolved gradually over the next few months. Based on case reports and the drug's pharmacokinetic profile, a high index of suspicion for ticlopidine-induced jaundice is prudent in patients with recent exposure to the agent who have evidence of liver damage.

Diagnosis of colon cancer by lavage cytology with an orally administered balanced electrolyte solution.

OBJECTIVE: We wished to evaluate the feasibility of colon lavage cytology using an orally administered balanced electrolyte solution. METHODS: Thirty-three patients undergoing colonoscopy for suspected colorectal cancer were entered into the study. Fifteen of these patients eventually had pathological confirmation of colorectal cancer, and one patient had prostatic adenocarcinoma with invasion of the rectum. The other 17 patients had no colonoscopic evidence of neoplasm and therefore served as controls. Prior to colonoscopy, patients received 10 mg of bisacodyl by mouth and enough Colyte to produce a clear anal effluent for cytological examination. The colon lavage cytology was interpreted by a cytopathologist blinded to the clinical features of each case. RESULTS: In 14 of 15 (93%) cases of biopsy proven colorectal cancer, the lavage cytology was positive: 10 cases demonstrated adenocarcinoma cells and four cases showed dysplastic cells. In contrast, the cytology was negative for dysplastic or malignant cells in the control patients. CONCLUSIONS: Colon lavage cytology using an orally administered balanced electrolyte solution provides acceptable specimens for cytological evaluation and had a 93% sensitivity and 100% specificity in our population.

Phlegmasia cerulea dolens as a complication of percutaneous insertion of a vena caval filter.

Unsuccessfully treated iliofemoral venous thrombosis can result in pulmonary embolism, phlegmasia cerulea dolens, and post-thrombotic syndrome. Phlegmasia cerulea dolens is characterized by tense swelling of the lower extremity with tenderness of the thigh over the femoral vein, mottling of the limb, and absent distal pulses. Without treatment, phlegmasia cerulea dolens can progress to cause venous gangrene and ultimate limb loss. In the reported case, phlegmasia cerulea dolens developed in a middle-aged woman with metastatic thyroid carcinoma following Greenfield filter placement via the femoral vein after heparinization for deep-vein thrombophlebitis had failed.

Prediction of variceal hemorrhage: a prospective study.

Prophylactic therapy to prevent the first variceal hemorrhage ceased being recommended for any cirrhotic because risks outweighed benefits. In this study, we identified cirrhotics that have never bled who are most prone to hemorrhage from varices. We developed a numerical grading system which combined size with other endoscopic characteristics, so varices would get an aggregate grade of 1 to 10. Varices were classified as either high grade (scored greater than or equal to 8) or low grade (scored less than or equal to 7). The grading system had a predictive value for bleeding when studied prospectively for a mean duration of 26 months in 52 patients subjected to placebo (15 patients) or various treatments (37 patients) in a randomized trial. High grade varices had a significantly higher association with bleeding than did low grade varices; 73% versus 7% (p less than 0.001) analyzing all 52 patients (of which 21% bled), and 83% versus 11% (p less than 0.05) analyzing the 15 placebo-treated patients (of which 40% bled). An esophagram positive for varices proved to be a sensitive screen for high grade varices, picking up 91% of them. However, it was a poor predictor of bleeding (one-third bled), since only 45% of radiologically evident varices were high grade. Since almost all cirrhotics with high grade varices can be expected to bleed within 2 yr, this group should be the focus of controlled trials to determine whether low risk prophylactic therapies reduce the incidence of first variceal hemorrhage.

Biphasic control of polymorphonuclear cell migration by Kupffer cells. Effect of exposure to metabolic products of ethanol.

In order to investigate the role of the Kupffer cells in the regulation of the inflammatory reaction seen in alcoholic hepatitis, rat liver Kupffer cells were cultured and exposed to products of ethanol metabolism. The resultant supernatants were tested to study their ability to stimulate or inhibit polymorphonuclear cell chemotaxis. Kupffer cells produced increased chemokinetic activity for human polymorphonuclear leukocytes (84 +/- 6 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p less than 0.01); when incubated with soluble products of microsomal peroxidation, the Kupffer cells engendered more chemokinetic activity than that produced by untreated Kupffer cells (106 +/- 6 vs. 84 +/- 6 cells per 5 high power fields; p less than 0.05). When Kupffer cells were incubated with acetaldehyde, the chemokinetic activity that appeared in the supernatant did not differ from control (51 +/- 3 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p = NS). Chemotaxis of polymorphonuclear cells was not observed when the Kupffer cell supernatants were tested by checkerboard analysis. Kupffer cells released a factor which, at different concentrations, inhibited the response of polymorphonuclear cells to the synthetic polypeptide chemotactic factor f-met-leu-phe by 47% (p less than 0.001). This effect was unchanged when the cells were exposed to acetaldehyde or to soluble products of microsomal peroxidation. Our results demonstrate that Kupffer cells are capable of stimulating or inhibiting polymorphonuclear cell chemotaxis and that some of these effects may be influenced by the products of ethanol metabolism, suggesting that Kupffer cells may play an important role in the regulation of the inflammatory reaction seen in alcoholic hepatitis.

Balloon cytology in screening of asymptomatic alcoholics for esophageal cancer, Part I.

We assessed the feasibility of using balloon cytology to screen an asymptomatic group of alcoholics at increased risk for esophageal cancer. The results indicate that this group can be studied with minimal morbidity and that useful material can be obtained in 85% of subjects. Keratinization was present in 68% of specimens and fungus was noted in 9%. Individuals with moderate to large amounts of keratinization consumed significantly more alcohol than those without cytologic evidence of keratin. We speculate that keratinization and fungus may represent markers of enhanced malignant potential in this population.

Mammalian collagenase increases in early alcoholic liver disease and decreases with cirrhosis.

To determine if alterations in collagen degradation may contribute to the pathogenesis of fibrosis and cirrhosis, we studied the hepatic collagenase activity of 20 baboons given alcohol containing diets or control diets under carefully controlled experimental conditions. We also studied 28 patients whose livers were biopsied for diagnostic purposes. Hepatic collagenase activity was significantly increased in baboons with fatty liver compared to levels in normal, control fed animals [(1.98 +/- 0.19 vs 1.20 +/- 0.08 units (microgram collagen digested/hour/mg liver protein) +/- S.E.M., p less than 0.001)]. The increase in hepatic collagenase activity persisted at the stage of fibrosis when compared to the activity in control baboons (2.16 +/- 0.07 vs 1.20 +/- 0.08 units +/- S.E.M., p less than 0.001). A single cirrhotic baboon available for study had an hepatic collagenase activity of 1.58 units. Patients with hepatic fibrosis had significantly higher hepatic collagenase activity than those with fatty livers [(9.12 +/- 0.94 (n =14) vs 4.52 +/- 0.54 (n = 7) units +/- S.E.M., p less than 0.001)]. However, in the group with cirrhosis, hepatic collagenase was lower [(3.92 +/- 0.61 (n = 7) units +/- S.E.M., p less than 0.001)] than in the group with fibrosis. Our findings suggest that the development of cirrhosis is coincident with, or favored by a failure of hepatic collagen degradative enzymes to keep pace with hepatic collagen synthesis.

Direct measurement of neutral collagenase activity in homogenates from baboon and human liver.

Neutral collagenase (EC 3.4.24.7) has been detected in human liver biopsies, baboon liver for the first time. The reaction mixtures were composed of collagen in solution and total liver homogenate in 0.5 M Tris-HCl, pH 7.5 at 25 degree C/0.2 M NaCl/10 mM CaCl2/3 mM p-chloromercuribenzoic acid. Collagenase activity was found by directly subjecting the reaction mixtures to viscometric assay and the activity was confirmed to be due to neutral collagenase by identifying the products using disc gel electrophoresis. It proved necessary to use p-chloromercuribenzoic acid in order to reveal collagenase activity in total liver homogenates from these species. The p-chloromercuribenzoic acid served to inhibit thiol proteinases and all other signs of nonspecific collagenolysis on disc gel electrophoresis, and it was able to activate latent collagenase which trypsin could not.

High blood acetaldehyde levels after ethanol administration. Difference between alcoholic and nonalcoholic subjects.

Blood actaldehyde and ethanol levels were measured in 11 subjects, six with chronic alcholoism and five nonalcholic controls, after alcohol had been given intravenously. Despite a progressive fall in blood ethanol over a range of 54 to 33 mM/acetaldehyde did not decrease in any of the 11 subjects. The mean acetaldehyde plateau level was significantly (p less than 0.001) higher in alcoholic (42.7 plus or minus 1.2 mum) than in nonalcoholic (26.5 plus or minus 1.5 mum) subjects. When the mean blood ethanol concentration reached 24 mM,the acetaldehyde plateau ended abruptly in each subject. The ethanol concentration at which this fall of blood acetaldehyde occurred suggests desaturation of an ethanol oxidizing system other than alcohol dehydrogenase and indicates that at high ethanol blood levels, such a system contributes to ethanol oxidation. The highet acetaldehyde levels in alcholism may result from both greater activity of this system and mitochondrial damage, and could contribut to the neurologic, hepatic and cardiac complications of alcoholism.

Effect of chronic alcohol consumption on ethanol and acetaldehyde metabolism.

Hepatic metabolism of ethanol to acetaldehyde by the alcohol dehydrogenase (ADH) pathway is associated with the generation of reducing equivalents as NADH. Conversely, reducing equivalents are consumed when ethanol oxidation is catalyzed by the NADPH dependent microsomal ethanol oxidizing system (MEOS). Since the major fraction of ethanol metabolism proceeds via ADH and since the oxidation of acetaldehyde also generates NADH, an excess of reducing equivalents is produced. This explains a variety of effects following acute ethanol administration, including hyperlactacidemia, hyperuricemia, enhanced lipogenesis and depressed lipid oxidation. To the extent that ethanol is oxidized by the alternate MEOS pathway, it slows the metabolism of other microsomal substrates. Following chronic ethanol consumption, adaptive microsomal changes prevail, which include enhanced ethanol and drug metabolism, and increased lipoprotein production. Eventually, injury develops with alterations of the rough endoplasmic reticulum and structural and functional abnormalities of the mitochondria.