James W. Freston

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase Unified List Based on International Collaborative Work

Background: Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.Objective: (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase™).Data Sources and Extraction: (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase™, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, ‘overall liver injury’ and ‘ALF’. EBGM of ≥2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of ‘overall liver injury’ and ‘ALF’ calculated from VigiBase™.Data Synthesis: After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase™, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of ‘overall liver injury’ and 83.1% were associated with at least one reported case of ALF.Conclusions: This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Drugs Five Years Later: Cimetidine: II. Adverse Reactions and Patterns of Use

Numerous adverse reactions have been attributed to cimetidine, which is understandable in view of the attention and scrutiny the drug has received, its widespread use, and its systemic effects. The reported frequency of side effects has differed considerably but is surprisingly low in all studies. The drug has caused an array of central nervous system disturbances, gynecomastia, and, rarely, hepatotoxicity, interstitial nephritis, bradycardia, hypotension, and even cardiac arrest. The last complication has occurred with rapid-bolus intravenous injection. Blood dyscrasias have also been rare and usually associated with serious underlying disease or multiple drugs, making it difficult to establish cause and effect in most cases. The drug is used widely to treatment conditions for which it is not approved. Some of these conditions are now believed to respond to cimetidine (gastric ulcer); others are known not to respond (acute upper gastrointestinal bleeding and acute pancreatitis).

Drugs Five Years Later: Cimetidine: I. Developments, Pharmacology, and Efficacy

: Cimetidine therapy has proved to be effective in healing most duodenal ulcers and in reducing the frequency of reulceration. It is unclear if low-dose maintenance therapy is superior to intermittent full-dose therapy in managing patients whose ulcers recur. Cimetidine is the preferred treatment for patients with the Zollinger-Ellison syndrome, and current evidence indicates efficacy in healing benign gastric ulcers. Some patients with reflux esophagitis improve with cimetidine treatment, but the drug cannot be regarded as first-time therapy. Largely circumstantial evidence suggests a role in preventing bleeding from acute gastric erosions and in preventing the acid aspiration syndrome. Cimetidine therapy has not been found to be useful in controlling acute upper gastrointestinal hemorrhage, acute pancreatitis, or several other conditions for which H2 blockade has been advocated.

Management of heartburn in a large, randomized, community-based study: comparison of four therapeutic strategies

OBJECTIVE:Our objective was to compare four management strategies for heartburn: therapy with an H2-receptor antagonist (ranitidine), therapy with a proton pump inhibitor (lansoprazole), crossover from ranitidine to lansoprazole (“step-up” therapy), and crossover from lansoprazole to ranitidine (“step-down” therapy).METHODS:This was a controlled, double-blind, multicenter trial comprising 593 adults with heartburn, randomized to one of four groups for 20 wk. Subjects received either ranitidine 150 mg b.i.d. for 20 wk, or lansoprazole 30 b.i.d. for 8 wk followed by lansoprazole 30 mg once daily for 12 wk (“step-up”), or lansoprazole 30 mg once daily for 8 wk followed by ranitidine 150 mg b.i.d. for 12 wk (“step-down”). Outcome measures were based on self-reports in daily diaries of 24-h heartburn severity, measured by maximum daytime and nighttime severity, and percentage of 24-h heartburn-free days measured by absence of both daytime and nighttime heartburn.RESULTS:Median heartburn severity was significantly lower (p < 0.05) for lansoprazole (0.25) than the other groups (0.46 ranitidine, 0.44 “step-up,” 0.35 “step-down”). The lansoprazole group had a significantly higher percentage of 24-h heartburn-free days (median 81.4%, p < 0.01) than other groups (66.6, 66.9, and 73.6%, respectively). In the “step-up” and “step-down” groups, heartburn was less severe, and percentages of 24-h heartburn-free days were higher during lansoprazole treatment regardless of treatment sequence.CONCLUSION:Proton pump inhibitor treatment provides more consistent heartburn relief than an H2-receptor antagonist, or “step-up” or “step-down” therapy.

Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury

BACKGROUND & AIMS Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Chemical Structure of Erythromycin and Hepatotoxicity

Abstract The biochemical features of erythromycin estolate essential for hepatotoxicity were studied in a patient with proved erythromycin estolate toxicity. The only two variables in commercial er...

Cimetidine and granulocytopenia.

Excerpt Cimetidine already is used extensively in the United States and abroad. This histamine H2-receptor antagonist was approved by the Food and Drug Administration (FDA) in August 1977 for the t...

Omeprazole, Hypergastrinemia, and Gastric Carcinoid Tumors

The long-term management of reflux esophagitis is challenging because of the frequency of symptomatic relapses and the uncertain efficacy and safety of long-term treatment with acid-suppressing drugs. Reflux esophagitis recurs within 6 months in at least 80% of patients after discontinuation of medical therapy [1]. Thus, some patients, such as those described in this issue by Klinkenberg-Knol and colleagues [2], require continuous therapy with omeprazole. Despite its superior efficacy when compared with histamine-2-(H2) receptor antagonists in healing reflux esophagitis [3] and maintaining remissions [4], clinicians have generally been reluctant to treat patients chronically with omeprazole because of concerns about the long-term effects of omeprazole-induced hypergastrinemia. Omeprazole also is superior to H2-receptor antagonists in healing gastric and duodenal ulcers [3] and is effective in combination with amoxicillin in eradicating Helicobacter pylori infection [5], but the hypergastrinemia associated with such short-term use appears to be of little consequence. Because gastrin secretion by the G cells of the antral mucosa is inhibited by an acid pH in the gastric lumen, hypergastrinemia may be induced by any treatment that decreases gastric acidity. For example, the administration of H2-receptor antagonists causes an increase in plasma gastrin levels proportional to the dose [6]. Omeprazole administration causes a greater increase because it is a more potent inhibitor of gastric acid secretion [7]. Plasma gastrin levels increase within days of starting omeprazole therapy and peak at 2 to 4 months, after which they generally remain stable at 2 to 4 times the baseline levels [2, 6-9]. Gastrin levels remain within the normal range of up to 100 ng/L in most persons, but an occasional patient may have levels more than 10-fold the normal level. Levels greater than 500 ng/L were found in 10 of 91 (11%) patients by Klinkenberg-Knol and colleagues [2] and in 2 of 31 (6.5%) patients [10] and 4 of 74 (5.4%) patients [9] in similar long-term studies. All 10 patients described by Klinkenberg-Knol and colleagues had increased gastrin levels before omeprazole administration, presumably caused by previous treatment with high doses of H2-receptor antagonists, and all had gastric retention of food, indicating the presence of a gastric motility disturbance. In some patients, the disturbance appeared to be related to previous gastric surgery. The gastric retention of food presumably enhanced gastrin release, thereby exacerbating the hypergastrinemia. The concern with sustained hypergastrinemia relates largely to the trophic effect of gastrin on the oxyntic mucosa of the stomach, a phenomenon shown in rat gastric enterochromaffin-like cells. Rats given large doses of omeprazole [11] or ranitidine [12] throughout life developed hyperplasia of enterochromaffin-like cells that progressed in some rats to gastric carcinoid tumors. This effect is now known to be caused by hypergastrinemia and can be produced by nonpharmacologic methods that induce hypochlorhydria and hypergastrinemia, such as subtotal resection of the gastric fundus [13]. Gastric enterochromaffin-like cell carcinoid tumors have been reported in patients with massive hypergastrinemia because of pernicious anemia [14] and the Zollinger-Ellison syndrome [15] but so far not with omeprazole treatment maintained for up to 5 years [2, 8, 9]. The study by Klinkenberg-Knol and colleagues confirms previous reports of long-term treatment studies [8, 9] that found hyperplasia of enterochromaffin-like cells but no evidence of dysplasia, carcinoid tumors, or other neoplastic changes. It does not necessarily follow that the hyperplasia in patients treated with omeprazole will progress to gastric carcinoid tumors, as seen in rats and in patients with pernicious anemia or the Zollinger-Ellison syndrome. Rats have an unusually high density of enterochromaffin-like cells and have an exaggerated gastrin response to achlorhydria [16]. Long-term omeprazole therapy given to species with lower densities of these cells (such as guinea pigs, hamsters, dogs, and mice) has not caused carcinoid tumors [16]. Patients with pernicious anemia generally have gastrin levels several times higher than those of patients receiving omeprazole [7], and those who developed carcinoid tumors had pernicious anemia for many years. In 123 patients with pernicious anemia, gastric carcinoid tumors were found by endoscopy in 5 (4%) who had a diagnosis of pernicious anemia for a mean duration of 19 years [14]. Thus, massive hypergastrinemia for many years appears to be necessary for tumors to develop in humans. Nearly all gastric carcinoid tumors in patients with the Zollinger-Ellison syndrome have developed in those with the multiple endocrine neoplasia I syndrome [17] despite the fact that gastrinomas are far more common in patients without the multiple endocrine neoplasia I syndrome. This observation has raised the possibility that the multiple endocrine neoplasia I gene itself is a cofactor along with massive hypergastrinemia for causing gastric carcinoid tumors in patients with the Zollinger-Ellison syndrome [17]. Data indicate that the enterochromaffin-like cell hyperplasia described by Klinkenberg-Knol and colleagues and others [2, 18, 19] may not be a drug effect. A unique study in Estonian patients with gastric ulcer disease who were not treated with antisecretory agents found that hyperplasia developed during a 4-year period [19]. The hyperplasia appeared to be a manifestation of selective preservation of enterochromaffin-like cells, whereas surrounding cells became atrophic during the progression of chronic gastritis to chronic atrophic gastritis, presumably because of H. pylori infection. Similar histologic changes were reported by Klinkenberg-Knol and colleagues, supporting the belief that the hyperplasia may not have been caused entirely by omeprazole-induced hypergastrinemia. The only way to be certain of this is to do a long-term controlled study of patients treated and not treated with omeprazole; such a study is unlikely to be done for ethical reasons, given the frequency of symptomatic relapses in patients with reflux esophagitis. Given the diminishing concern about omeprazole-induced hypergastrinemia, should clinicians bother to monitor gastrin levels during continuous omeprazole therapy for long periods? Frequent monitoring would add cost but little value in view of the lack of therapeutic options for patients with high gastrin levels [20] and the infrequency of very high levels. Switching to standard doses of H2-receptor antagonists, such as 150 mg of ranitidine twice daily, is an unsatisfactory option because it results in relapses in nearly 90% of patients within 1 year [4]. High doses of H2-blockers should be effective in preventing relapses, but this has never been documented. In any case, this approach would be expected to cause increases in gastrin levels in proportion to the increased degree of acid suppression. Decreasing the omeprazole dosing regimen to 20 mg three times a week is also untenable because it is associated with a 50% increase in relapses within 6 months [21]. Antireflux surgery is appealing in young patients who otherwise face a lifetime of medical treatment, but it is important to select a surgeon with considerable experience and documentation of good results because successful antireflux surgery is highly operator-dependent. Because the frequency of high gastrin values (greater than 500 ng/L) has been no higher than 11% in three studies [2, 9, 10] of long-term omeprazole use, a conservative and inexpensive compromise would be to measure gastrin levels after 1 year of continuous therapy. This is as likely to detect gastrin levels greater than 500 ng/L as are three separate measurements during the year [20]. If such levels are recorded, it could signify the development of chronic atrophic gastritis; this would diminish acid secretion, and the patients might no longer require omeprazole. As shown by Klinkenberg-Knol and colleagues [2], such patients could also have a gastric motility disturbance, which might respond to the addition of a prokinetic agent such as cisapride (Propulsid; Janssen Pharmaceutica, Titusville, New Jersey), although this remains to be determined. Thus, the specter of hypergastrinemia does not seem to be great enough to dissuade clinicians from using long-term omeprazole therapy in appropriately selected patients.

Membrane damage and the pathogenesis of cardiomyopathies

Membrane damage plays an important role in the pathogenesis of ischemic damage to the myocardium, and is ultimately responsible for the release of cellular contents-notably intracellular enzymes-after ischemic cell death. This membrane damage may be caused by the incorporation of lipids into myocardial membranes, by the enzymatic actions of lipases that hydrolyze membrane phospholipids, and by free radicals that are produced in the ischemic myocardium. Much less is known of the role of membrane damage in the cardiomyopathies, but direct myocardial membrane damage may occur in some specific forms of this diverse class of diseases. Direct membrane effects of exogenous substances are likely to be of pathogenic significance in alcoholic and some toxic cardiomyopathies, for example those produced by hydrocarbons and adriamycin. Membrane damage may also play a role in the pathogenesis of viral cardiomyopathies, due possibly to incorporation of viral components into the cardiac sarcolemma where these foreign materials can serve as antigens that direct host responses to attack the cells of the heart.

Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US.

AbstractBackground/aims: Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide). Methods: Patients were randomized to receive either pioglitazone (15–45 mg once daily) or glibenclamide (5–15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 × ULN) with a secondary endpoint of 8×ULN. Main results: The intent-to-treat population included 1051 pioglitazonetreated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 ×ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 × ULN + total bilirubin 2 × ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 × ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p ≤0.05) fewer cases of ALT >1.5 × ULN, aspartate aminotransferase >1.5 × ULN and g-glutamyl transpeptidase >1.5 × ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported. Conclusion: This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes.Trial registration number (clinicaltrials.gov): NCT00494312