Outcome, comorbidity, hospitalization and 30-day mortality after closure of acute perforations and postoperative anastomotic leaks by the over-the-scope clip (OTSC) in an unselected cohort of patients.

BACKGROUND: Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC). METHODS: Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity. RESULTS: In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively. CONCLUSIONS: In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.

Antihypertensive effects of doxazosin in systemic hypertension and comparison with terazosin.

A multicenter, double-blind study compared the antihypertensive efficacy and safety of doxazosin and terazosin as once-daily therapy. Doxazosin, a potent antihypertensive agent, selectively inhibits alpha 1 adrenoceptors. Its pharmacokinetic profile, including gradual onset of action, long plasma elimination half-life and long duration of action, permits once-daily dosing. Terazosin, a structural analog of prazosin, also inhibits alpha 1 adrenoceptors and is recommended as once or twice-daily therapy. Nineteen (73%) of 26 patients randomly assigned to receive doxazosin were therapeutic successes; 17 (65%) achieved normalized blood pressure (defined as blood pressure less than or equal to 90 mm Hg). The mean final daily dosage in patients classified as therapeutic successes was 2.4 mg. Eighteen (64%) of 28 terazosin-treated patients were considered therapeutic successes; 16 (57%) achieved normalized blood pressure. The mean final daily dosage in patients classified as therapeutic successes was 5.6 mg. Treatment-related side effects were observed in 30% of doxazosin-treated and 39% of terazosin-treated patients. Most side effects observed in either treatment group were mild or moderate and either disappeared or were tolerated with continued therapy. Doxazosin is an effective, well-tolerated, once-daily antihypertensive agent; it is comparable with terazosin but at a lower daily dosage.

Adverse drug reactions in patients with gastroenterological diseases: does age increase the risk?

BACKGROUND: It has been claimed that the risk of adverse drug reactions increases with age. However, only limited data exist for disease-group specific risks and none for patients with liver and gastrointestinal diseases. AIMS: To determine the incidence and characteristics of adverse drug reactions and the physicians' awareness of adverse drug reactions. METHODS: During a 7-month period, a prospective survey of 532 male patients (158 aged 65 years or older; 30%) was conducted on a hepatogastroenterological ward of a tertiary-care university hospital, using intensive bedside and computer-assisted drug surveillance methods. RESULTS: No difference was found in the overall rate of adverse drug reactions between older and younger patients (25.9% vs. 24.2%) during 6213 treatment days. However, a significantly higher risk for developing adverse drug reactions could be shown for the elderly with biliary tract diseases (P < 0.01). Independently of age, patients suffering from gastric ulcers, acute episodes of pancreatitis, cholangitis or inflammatory bowel diseases were at high risk of adverse drug reactions. Adverse drug reaction-associated mortality was encountered in four elderly and none of the younger patients. Secondary pharmacological effects and drug toxicity were the main types of adverse drug reactions for both age groups. Although 75.3% of the adverse drug reactions were predictable, only 37.5% of all adverse drug reactions were recognized by the staff physicians. CONCLUSION: In hepatogastroenterological patients, advancing age was not associated with an overall increased risk of adverse drug reactions except for patients with biliary tract diseases. In the elderly, adverse drug reactions were more severe and carried higher mortality. Guidelines and educational programs should be developed to increase the awareness of adverse drug reactions and their prevention, especially in high risk patients and, thus, to improve patient outcomes.

Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting.

OBJECTIVE: To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions. DESIGN: A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs. SETTING: This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997. PATIENTS AND PARTICIPANTS: 379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded. METHODS: All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction. RESULTS: Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year ($US59 600/year) [ 1999 values]. CONCLUSION: Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.

Risperidone-induced cholestatic hepatitis.

Risperidone, a widely used atypical and potent neuroleptic drug, is assumed to induce fewer hepatic side-effects than phenothiazine anti-psychotics. Recently, we observed a case of risperidone-induced cholestatic hepatotoxicity. A 37-year-old male developed a rapid increase in liver enzymes and cholestatic parameters after starting treatment with risperidone for paranoid psychosis. Work-up for other potential aetiologies was negative. The results of a percutaneous liver biopsy were consistent with drug-induced liver injury and cholestasis. Over the course of one month after the discontinuance of all anti-psychotic agents, the liver function test results returned to near-normal values. This observation supports the need to monitor cholestatic parameters in addition to liver function enzymes during initiation and the first weeks of risperidone intake.

Extracellular matrix proteins in human bile and gallstones.

OBJECTIVE: To investigate the presence of extracellular matrix (ECM) proteins in human bile and gallstones and to determine whether they play a role in gallstone formation. METHODS: ECM components [procollagen-III-peptide (P-III-P), laminin, and hyaluronic acid] in bile from patients with (n = 22) and without (n = 6) gallstone disease were investigated by immunoassay. Bile, gallstones, and serum were assayed for extracellular matrix components in an additional 19 patients with gallstone disease and gallstones were analysed in a third set of 26 patients. The expression of hyaluronic acid synthetase in bile duct and gall bladder epithelia was investigated by immunocytochemistry. RESULTS: Hyaluronic acid levels were significantly elevated in hepatic and gall bladder bile, but not in the serum of patients with compared with those without gallstone disease (137 versus 81 micrograms/l, respectively; P < 0.05). No differences were found between hepatic and gall bladder bile. Procollagen-III-peptide and laminin were detected in the hepatic bile of patients in both groups. Laminin levels were higher in gall bladder bile than in serum in all patients and measurable amounts of hyaluronic acid were found in gallstones. The amount of hyaluronic acid was inversely correlated to the volume of the gallstone, i.e., the smallest gallstones contained the highest levels of hyaluronic acid. No procollagen-III-peptide or laminin was found in the gallstones. Immunocytochemistry of the epithelial cells of bile duct and gall bladder mucosa stained strongly for hyaluronic acid synthetase. CONCLUSIONS: Hyaluronic acid as a progenitor of ECM can be detected in bile and is significantly elevated in patients with gallstone disease. Small gallstones contain more hyaluronic acid than large stones, suggesting that hyaluronic acid may play a role in gallstone formation, particularly since it is produced by the epithelial lining of bile ducts and is found in gall bladder mucosa.

Comparison of tree-based methods for prognostic stratification of survival data.

Tree-based methods can be used to generate rules for prognostic classification of patients that are expressed as logical combinations of covariate values. Several splitting algorithms have been proposed for generating trees from survival data. However, the choice of an appropriate algorithm is difficult and may also depend on clinical considerations. By means of a prognostic study of patients with gallbladder stones and of a simulation study, we compare the following splitting algorithms: log-rank statistic adjusted for measurement scale with (AP) and without (AU) pruning, exponential log-likelihood loss (EP), Kaplan-Meier (KP) distance of survival curves, unadjusted log-rank statistic (LP), martingale residuals (MP), and node impurity (ZP). With the exception of the AU algorithm (based on a Bonferroni-adjusted p-value driven stopping rule), trees are pruned using the measure of split-complexity, and optimally-sized trees are selected using cross-validation. The integrated Brier score is used for the evaluation of predictive models. According to the results of our simulation study and of the clinical example, we conclude that the AU, AP, EP, and LP algorithm may yield superior predictive accuracy. The choice among these four algorithms may be based on the required parsimonity and on medical considerations.

Changes in hypothalamic catechol-O-methyl-transferase during sexual differentiation of the brain.

1. An assay using [14C-methyl]-S-adenosyl-L-methionine was used to measure catecholamine-O-methyl-transferase (COMT) activity in the hypothalamus of newborn male and female rats from day 1 to day 12 and in adult animals after day 60. 2. There was no difference in COMT activity between sexes until day 8, when it became significantly higher in females. 3. Administration of 200 micrograms testosterone propionate to female rats at birth reduced the hypothalamic COMT level of the adult to that observed for male littermates. The response was dose-dependent in the range 50 to 200 micrograms. The hypothalamic content of COMT after puberty of male rats castrated at birth was comparable to that of post-pubertal females. 4. These results show that COMT, one of the enzymes involved in the control of brain biogenic amines, is also affected by the process of sexual differentiation of the brain.

Hypothalamic nuclei catechol-O-methyl-transferase and the process of brain sexual differentiation.

The present review focuses on some aspects of the function of catechol-O-methyl-transferase (COMT) in the hypothalamic control of gonadotrophin release by the pituitary gland. The in situ influence of a catecholestrogen (2 OH.E2) on the amount of COMT in the hypothalamic nuclei involved in such control as well as on the process of sexual differentiation of the brain is also discussed. Catecholestrogens do not play a significant role in the induction of sexual differentiation and the observed action is probably a pharmacological one. It is difficult to understand why a substance whose structure is so closely related to that of estrogen is so much less active. Most probably the estrogen receptor in the cytosol at this stage of development is not able to recognize the catecholestrogen. Since catecholestrogens are not true virilizing substances they may be used to assess the critical levels of enzymes which are required to determine the sexual pattern of hypothalamic activity. The fact that the extent of the changes in COMT content of the hypothalamus is related to the amount of hormone used to induce virilization strengthens the view that sexual differentiation is the consequence of a genomic change during the critical period, which will induce an enzymatic pattern characteristic of the male acyclic pattern of gonadotrophin control. The finding that the COMT content of the hippocampus also changes in parallel to sexual differentiation leads us to speculate that perhaps sexual behavior may also be differentiated in the same way.

[Technical and clinical success with extracorporeal shockwave lithotripsy in pancreatic duct calculi]. / Technischer und klinischer Erfolg der extrakorporalen Stosswellenlithotripsie bei Pankreasgangsteinen.

BACKGROUND: Chronic pancreatitis is often complicated by concrements obstructing the main pancreatic duct. Duct obstruction is discussed as potential mechanism responsible for recurrent and persistent pain. PATIENTS AND METHODS: 75 symptomatic patients (15 female, 60 male; 46 +/- 12 years) with stones in the main pancreatic duct (solitary n = 23; multiple n = 52) primarily not endoscopically extractable even after sphincterotomy of the pancreatic orifice were treated by means of a piezoelectric lithotripter (Piezolith 2500). Fragmentation and stone clearance were documented by ERP. The clinical benefit was evaluated in 35 patients (9 female, 26 male; 45 +/- 12 years) followed up meanwhile for more than 12 (29 +/- 14) months. RESULTS: After 3 +/- 2 (1 to 10) ESWL-sessions/patient the concrements were fragmented successfully in 80% of the patients. Focussing of the stones was achieved sonographically (15%), fluoroscopically (45%) or using both imaging techniques (40%). In total, 61% of the patients became stone free, 44% spontaneously, in further 17% all remaining fragments could be removed endoscopically. In 39% of the patients only a partial extraction was achieved. Severe complications due to shockwave application did not occur. The majority of the patients (stonefree n = 22, remaining fragments n = 13) followed up > or = 12 months kept free of pain (51%) or reported on pain relief (26%). Nine patients developed 13 recurrent calculi, which were again treated successfully by interventional measures in 8/9 patients. CONCLUSIONS: The data confirm the value of extracorporeal shockwave lithotripsy as an important tool in the interventional therapy of chronic pancreatitis. Even if recurrent calculi may occur, the majority of patients will experience at least a medium-term profit by those measures due to pain relief.

[Changes in and acceptance of surgical and noninvasive therapy procedures in cholecystolithiasis]. / Wandel und Akzeptanz operativer und nichtinvasiver Therapieverfahren bei Cholezystolithiasis.

BACKGROUND: The treatment of cholecystolithiasis has changed fundamentally in recent years due to the development of non-surgical techniques (extracorporeal shockwave lithotripsy [ESWL], oral litholysis) and the implementation of laparoscopic cholecystectomy. PATIENTS AND RESULTS: Retrospective analysis of 2270 patients (1649 women, 621 men; age: 47.2 +/- 14 years) presenting with gallstone disorders in a university medical outpatients department between 1988 and 1992 in order to be instructed as to the most suitable therapy method bear witness to the rapid change in therapeutic procedure. Laparoscopic removal of the gallbladder has virtually supplanted conventional cholecystectomy, and within 5 years the proportionate role of ESWL has declined from 21 to 12%. Over the years, the proportion of patients requiring no therapeutic intervention remained constant (at about 20%). The therapeutic recommendations of the "experts" were implemented in almost 80% of cases. The majority of patients were satisfied with the chosen therapeutic approach (surgery: 93.0%, ESWL: 77.6%), although 44% of ESWL-patients and 36% of surgically managed patients reported complaints which persisted even after completion of therapy. Despite unsuccessful ESWL (residual fragments or recurrent stones) 58/95 (61%) of interviewed patients would again give preference to this non-invasive modality in the event of a renewed therapeutic decision. CONCLUSION: Only a few years after its introduction, laparoscopic cholecystectomy has asserted itself as the predominant treatment option. But as far as acceptance and preference by the patient are concerned extracorporeal shockwave lithotripsy--as a non-invasive treatment modality--also enjoys high popularity and can be recommended as an alternative to surgery in suitable patients chosen according to the currently established stringent selection criteria.

[Oxidative stress and cardiovascular diseases]. / Oxidativer Stress und kardiovaskuläre Erkrankungen.

A number of diseases like hypercholesterolemia and atherosclerosis, hypertension, congestive heart failure, diabetes, ischemia-reperfusion, neurodegenerative diseases as well as acute and chronic inflammatory diseases are characterized by an increased steady-state concentration of reactive oxygen species (ROS). On a biomolecular level an enhanced oxidative stress causes damage of proteins, lipids and nucleic acids. Both the experimental and therapeutic efficiency of different antioxidative compounds (like various antioxidative enzymes) , drugs, metabolites and vitamins for the maintenance of an appropriate intracellular redox potential underline the importance of an excessive ROS-formation for these diseases. Control of excessive ROS-formation can be obtained by angiotensin converting enzyme (ACE-) inhibitors, by AT (1)-receptor blockers, by statins and other lipid lowering compounds, by improved expression of antioxidative enzymes (superoxide dismutase, catalase etc.), by compounds such as probucol, certain vitamins, pyruvate, by lipid apheresis and by physical exercise training, which displays surprising efficacy.

Antiviral effects of recombinant interferon alfa and clinical experience in viral infections.

Alpha interferons act virostatically by influencing several cellular enzymes involved in virus replication. The success of treatment with biosynthetic recombinant interferon alfa-2b (rIFN alfa-2b) has been confirmed in numerous clinical studies. Following intralesional injection, up to 56% of condylomata acuminata were totally eradicated. Laryngeal papillomatosis responded favourably to systemic therapy with various alpha-interferons, demonstrating complete remissions of up to 88%. Preliminary therapeutic trials using rIFN alfa-2b in chronic viral hepatitis (B, Delta, non-A, non-B) consistently showed beneficial effects on the disease-related biochemical, virological and histological parameters. Interferon alfa-2b proved particularly effective in the early stage of AIDS-associated Kaposi's sarcoma.

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: 1. There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. 2. In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. 3. Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clear-cut advantages as well.

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained-release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: (i) There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. (ii) In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. (iii) Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clearcut advantages as well.

Possible mechanism of action of 2-hydroxylated estradiol on the positive feedback control for LH release in the rat.

Evidence was given to support a positive role of 2-hydroxyestradiol on the LH surge. The catecholestrogen may act by its catechol A ring on the nucleus arcuatus COMT, consequently leaving the noradrenaline free. The result may be a longer action on the peptidergic terminal in the median eminence and an increase in the LH secretion by the pituitary. This assumption is supported by the observations that the catecholestrogen effect can be mimicked by homocystein, an aminoacid able also to inhibit COMT activity, having neither a steroid nor a catechol structure. The fact that alpha-MIT is able to prevent homocystein-induced increase in LH suggests that it is acting by protecting the local increase of the catecholamine. After ten years of intensive effort to understand the possible physiological role of the catecholestrogens, attention was mostly paid to its structural similarity to estrogen and a great deal of effort was made to understand its function by acting upon the estrogen receptor in the cytosol. The evidence for catecholestrogen action upon COMT, an outside membrane enzyme involved in the process of catecholamine degradation, supports the idea of a catechol action for 2-OHE2. The present evidence strongly supports the physiological importance of the catechol group in the 2-OHE2 in its action mechanism. However, a true physiological role for the catecholestrogens remains to be solved. The evidence we bring confirms once more that catecholestrogens may have a function and explains a new mechanism of action. However, the basic question concerning the true amount of catecholestrogen existing in the hypothalamic nuclei, either brought by the blood stream or locally produced, still needs to be solved: we cannot say whether the mechanism we described is a functioning one, whether it is just brought about by the experimental increase of the catecholestrogen or the artificial blockage of COMT.

Biliary elimination of non-steroidal anti-inflammatory drugs in patients.

In view of evidence in animals that enterohepatic recirculation of non-steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.