[Comparison of Two Symptom-Triggered Treatments for Alcohol Withdrawal: HAES vs. SAB-P]. / Zwei Alkoholentzugsscores im Vergleich: Hamburger Alkoholentzugs-Skala (HAES) vs. Scoregesteuerte Alkoholentzugsbehandlung nach Rating durch das Pflegepersonal (SAB-P).

INTRODUCTION: For alcohol withdrawal during hospitalization, often a medication as means for withdrawal needs to be chosen. Modern, score-controlled processes that can be used by the nursing staff after instruction by physicians are frequently not used and even unknown in hospitals. One reason for this is that some of the scores require checking several criteria and are therefore more time-consuming and complicated than use of a fixed-dosage strategy. The SAB-P and HAES are short with only 6 items that can be checked by the nursing staff. METHODS: Safety of the Hamburg Alcohol Withdrawal Scale (Hamburger Alkoholentzugs-Skala (HAES)) was analyzed retrospectively and prospectively with regard to score-controlled alcohol-withdrawal treatment after rating by the nurse staff (Scoregesteuerte Alkoholentzugsbehandlung nach Rating durch das Pflegepersonal (SAB-P)). RESULTS: Incidence of complications in patients treated with SAB-P and HAES was nearly similar with 1% start of delirium and 3% seizures (SAB-P) and 0.5 to 1.5% start of delirium and 0 to 0.5% seizures in the HAES group. With both scales it was possible to start medical treatment while still under falling alcohol levels (0.93 and 0.91%, respectively). Medication dosage was initially higher using the HAES, so that the time needed to monitor withdrawal symptoms could be reduced (3.8 vs. 3.1 days). DISCUSSION: Using a score-controlled strategy for alcohol withdrawal leads to a lower complication rate than found in literature. The structured procedure was helpful for the nursing staff as well as for the physicians. SAB-P as well as HAES made withdrawal for the patients more comfortable and led to fewer complaints. Because of rapid reaction and faster symptom reduction of HAES, there was less time necessary for monitoring. Simple handling, clomethiazol, oxazepam or diazepam as applicable medication and clear documentation are the advantages of HAES.

[Long-term prescription of benzodiazepines and non-benzodiazepines]. / Langzeitverschreibung von Benzodiazepinen und Non-Benzodiazepinen.

BACKGROUND: The number of persons with a dependence on prescription drugs such as sedatives or tranquilizers in Germany is estimated at between 1.4 and 1.9 million. According to national addiction treatment documentations only very few of them seek help in specialised treatment services. The majority of prescription drug-dependent people use benzodiazepines. This medication is usually prescribed by physicians and according to German guidelines it should be prescribed only for limited, short periods and in low doses. OBJECTIVE: This study aims to determine the extent of the problematic prescription of benzodiazepines and non-benzodiazepines. METHODS: We used prescription data from the Northern Germany Computing Centre for Pharmacies registered between 2005 and 2007. For the German regions of Hamburg, Bremen and Schleswig-Holstein, benzodiazepine prescriptions during an individual prospective period of 12 months were analysed. RESULTS: From July 2005 to June 2006, 294 143 prescriptions of benzodiazepines and non-benzodiazepines were recorded for 78 456 citizens of Hamburg and billed at the expenses of the governmental health insurance funds. In the course of one observed patient year, 51.1% of benzodiazepine prescriptions were in accordance with the German guidelines. 15.6% of the patients were supplied on a long-term basis (0.5-1 DDD during at least 2 months). Prescriptions for women and persons older than 70 years were disproportionately high. Compared with the Federal states of Bremen and Schleswig-Holstein, Hamburg does not show an exceptional position. CONCLUSION: The prescription of benzodiazepines which is not in accordance with the relevant national guidelines is widespread and calls for discussion and education among physicians and pharmacists. Furthermore, professional addiction services should reconsider ways to help and attract prescription drug-dependent people to cover their needs, as their numbers will grow in an aging society.

[Medication dependency and physician's role]. / Zusammenhang zwischen Verschreibungsverhalten der Arzte und Medikamentenabhängigkeit ihrer Patienten.

The administration of benzodiazepines in suicidal, anxious, or agitated patients with depression is common international practice. Nevertheless, the prescription of BZDs is recommended to be limited to a period of a few weeks. There are several epidemiological studies about the situation in Germany, but many questions are still unanswered. The BfArM sought a new method to track prescription of medications with the risk to induce dependency. The present article describes the methodology and the early results of the pilot study. As a new approach, data from a processing center for pharmacies were used; patient-years, a risk scale with six steps, and diazepam-equivalence dose instead of defined daily dose were used for the analysis. About 35% of prescriptions were long-term treatment. Even if several physicians prescribe the medication, the main physician prescribing the medication can identify the risk level of the patient in 80-90% of cases.

Leptin: a modulator of alcohol craving?

BACKGROUND: Leptin has been shown to regulate food intake and energy expenditure. Because leptin acts via regulation of appetite, we studied the hypothesis that suggests leptin modulates craving for alcohol as well. METHODS: We studied leptin plasma concentrations (RIA) both in alcoholic subjects during inpatient detoxification (day 1: n = 78, day 14: n = 60) and in healthy control subjects (n = 30). To rule out interference with the activation of the HPA axis during alcohol withdrawal, we also evaluated cortisol plasma levels (RIA). RESULTS: We found plasma leptin and cortisol elevated at onset of withdrawal, decreasing significantly up to day 14. Leptin (and the body-mass corrected ratio leptin/BMI) was highly correlated with self-rated craving. No correlations of craving with cortisol and BMI were observed. CONCLUSIONS: We suggest that leptin may modulate withdrawal-induced craving in alcoholic subjects.

Improvement of schizophrenic patients' subjective well-being under atypical antipsychotic drugs.

Recent research indicates that subjective well-being is a major determinant of medication compliance in schizophrenia. However, it is yet unresolved whether atypical neuroleptics differ regarding subjective side-effects. A self-report instrument has been constructed to evaluate 'subjective well-being under neuroleptics' (SWN). The primary aims of the present study were to develop a short form of the SWN and to investigate the extent to which the atypical antipsychotic improves the patient's subjective well-being. The short form of the SWN was constructed following an item analysis based on data from 212 schizophrenic patients medicated with either typical or atypical antipsychotics. The short form of the SWN showed sufficient internal consistency and good construct validity. The SWN was only moderately correlated with positive and negative syndrome scale (PANSS) scores or changes in psychopathology (r=-0.20 to -0.37). SWN-ratings in patients receiving olanzapine were superior compared to those of patients medicated with either clozapine or risperidone on three of five domains of well-being. Clozapine reduced global psychiatric symptoms significantly more than risperidone. It is concluded that the assessment of subjective well-being under antipsychotic treatment provides an independent outcome measure which is relevant to compliance.

[Open studies in comparison to controlled studies in testing of neuroleptics]. / Aussagekraft offener Studien im Vergleich zu kontrollierten Studien in der Prüfung von Neuroleptika.

OBJECTIVE: Due to methodological reservations, results concerning the efficacy of neuroleptics in open trials are often regarded with doubt. Until now, there are nearly no studies comparing findings of controlled double-blind with those of open trials. Aim of this study was to investigate if results of an open or double-blind approach differ and hereby to gain information about the validity of open trials. METHODS: After a literature research, five neuroleptics were identified for which at least 3 open and 3 double-blind trials exist which met the inclusion criteria and from which either the reduction of the BPRS (Brief Psychiatric Rating Scale)-score or the response rate could be determined. RESULTS: There were no differences in the reduction of the BPRS-score or response rate for all 5 neuroleptics between open and double-blind trials. Furthermore, the efficacy of all 5 neuroleptics was comparable. CONCLUSIONS: Double-blind controlled studies are essential in the investigation of new compounds. But results of methodologically well performed open studies are valid and deserve more attention. Preceding open trials may help in the design of double-blind studies.

Apolipoprotein A-I in bile inhibits cholesterol crystallization and modifies transcellular lipid transfer through cultured human gall-bladder epithelial cells.

BACKGROUND: Apolipoprotein A-I (Apo A-I), conventionally purified by several steps including organic solvent-delipidation from plasma, inhibits cholesterol crystallization in bile. To observe a significant effect in vitro, however, supraphysiological concentrations above 100 microg/mL are required. For this reason, this protein has not been considered to play a physiological role in vivo. In the present study, we examined the cholesterol crystal growth-inhibiting effect of biliary Apo A-I at its physiological concentration, the modification of transcellular transfer of biliary lipids through cultured human gall-bladder epithelial cells (GBEC) by Apo A-I at its physiological concentration and the binding and secretion of Apo A-I by GBEC. METHODS AND RESULTS: We purified biliary Apo A-I to near homogeneity using immobilized artificial membrane chromatography. At 5 microg/mL, biliary Apo A-I reduced cholesterol crystal mass by 50%, whereas plasma-derived, solvent-delipidated Apo A-I had no effect. Using an antibody-capture enzyme-linked immunosorbent assay, we found reduced Apo A-I concentrations in bile samples from gallstone patients when compared with bile samples from gallstone-free controls (medians, 2.35 and 9.4 microg/mL, respectively). In a GBEC line, Apo A-I (5 microg/mL) enhanced transfer of phospholipid and cholesterol from the mucosal to the serosal side of cell monolayers by approximately 50%. These cells appear to bind Apo A-I reversibly in a dose- and time-dependent manner, compatible with receptor-type binding. Cultured human gall-bladder epithelial cells also showed basal secretion of Apo A-I, which was greatly increased by exposure to model bile solutions. CONCLUSIONS: Apolipoprotein A-I in bile, thus, has both a direct effect on cholesterol crystal formation and enhances lipid removal from gall-bladder bile by GBEC. This effect may be specific and receptor mediated. These observations support two separate roles for human biliary Apo A-I and suggest that this protein may be important in preventing the formation of cholesterol crystals (the initial step in gallstone formation) in supersaturated bile.

Suicide attempts with mirtazapine overdose without complications.

BACKGROUND: One important aim of pharmacotherapy in depressed patients is the prevention of suicide attempts. Therefore, the medication given should be efficient and safe in overdose. RESULTS: We saw two patients after they had overdosed with mirtazapine because of suicidal intention. Both patients had taken 30 and 50 times a normal daily dose and achieved a full recovery without any complications or harm. CONCLUSIONS: Mirtazapine seems to be a safe compound in overdose. Therefore, it is an important therapeutic agent in depressed and suicidal patients.

Human gallbladder mucosal function: effects on intraluminal fluid and lipid composition in health and disease.

Gallbladder mucosal absorption of fluid during fasting is a well-known process. Indirect in vivo and recent in vitro evidence for physiologically relevant gallbladder absorption of cholesterol and phospholipids from bile has been observed in humans. The present study explored and compared by indirect means the relative efficiences of human gallbladder mucosal absorption of fluid and lipids in health and disease. Biliary lipids and pigment content were measured in fasting gallbladder bile samples obtained from gallstone-free controls and from four study groups: multiple and solitary cholesterol gallstone patients, and morbidly obese subjects with and without gallstones. Bile salts and pigment content were significantly greater in gallstone-free controls than in all other disease study groups. This was interpreted as evidence of more effective gallbladder mucosal fluid absorption in nonobese gallstone-free controls compared to that in all other groups. Correlation plot analyses of biliary lipids showed lower concentrations of phospholipids than expected from the index bile salt concentrations. The same was found for cholesterol concentrations but only in supersaturated samples. These findings were much more pronounced in gallstone free-controls and were accordingly interpreted as evidence of more efficient gallbladder absorption of both phospholipids and cholesterol in controls compared with that found in each of the disease study groups. Moreover, impaired gallbladder mucosal function, while invariably associated with cholesterol gallstone disease, was not found to be a necessary consequence of the physical presence of stones. It is concluded that efficient gallbladder mucosal absorption of both fluid and apolar lipids from bile is a normal physiological process that is often seriously impaired in the presence of either cholesterol gallstone disease or at least one of its precursor forms.

Variations in pigment and carbohydrate content of gallbladder bile affect accurate quantitation of total protein when using the fluorescamine method.

BACKGROUND: Despite solute dilution and reduced total lipid concentrations, an unexplained increase in protein concentration has been reported to occur in the gallbladder bile of cholesterol gallstone patients. METHODS: Solutes in gallbladder bile from gallstone-free controls and from four study groups were measured using standard methods. Total proteins were measured using amino acid analysis and a conventional fluorescamine method. RESULTS: Bile salts and pigment content were greater in gallstone-free controls than in all other study groups, including morbidly obese gallstone-free subjects. Total biliary protein concentration, as determined by amino acid analysis in the gallstone-free control group was higher than in non-obese gallstone patients with multiple stones and in morbidly obese gallstone-free subjects. Total biliary proteins as measured with fluorescamine, however, did not show intergroup differences. A major problem of the conventional fluorescamine assay is shown to be an artefact arising from the high pigment content of the more concentrated samples. CONCLUSIONS: Very dilute gallbladder bile samples are often found in the presence of gallstone disease. This also occurs in morbidly obese subjects, even in the absence of gallstones. Although the contribution of protein secretion/absorption by the gallbladder can also be relevant, especially in the presence of morbid obesity, the protein concentration in gallbladder bile, when accurately measured, generally parallels the concentrations of non-absorbed biliary solutes, reflecting the efficiency of fluid absorption. Measurement of biliary proteins by the conventional fluorescamine method is unreliable in clinical studies in which intergroup differences in pigment content are commonly present.

[Role of biliary proteins in pathogenesis of cholesterol gallstones]. / Die Rolle biliärer Proteine in der Pathogenese von Cholesteringallensteinen.

Cholelithiasis is a frequent disease in developed countries with significant economical implications. While the multifactorial pathogenesis of cholesterol gallstones has been widely accepted, the relative importance of the various contributing factors is not yet clear. One focus of research in recent years has been the identification and functional analysis of biliary proteins. Few proteins are synthesized in the biliary tract itself, the majority reflect the composition of serum proteins. Many biliary proteins modify cholesterol crystallization, the initial step of cholesterol gallstone formation. In cholelithiasis, biliary concentration of many pronucleating proteins are increased. However, this may be a consequence rather than the cause of the disease, because a majority of these proteins are acute-phase reactants. They may be secreted into bile at increased concentrations because of--often asymptomatic--cholecystitis due to gallstone disease. A number of protein-lipid interactions have been observed in search of a mechanism of action of biliary effector proteins. Only recently the potential modification of lipid removal from gallbladder bile by Apo A-I was described in addition to its direct antinucleating effect. In conclusion, biliary proteins directly modify cholesterol crystallization by protein-lipid interactions and may influence lipid absorption from the gallbladder.

Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene.

Genetic factors are supposed to play a major role not only in the etiology of psychiatric disorders but also in individual response to medications. To test the hypothesis that inter-individual differences in response to clozapine and the occurrence of side-effects might be influenced by variations in the dopamine D4 receptor gene, we examined frequencies of four known polymorphic sites affecting protein structure in the dopamine D4 receptor gene in 149 patients with schizophrenia or schizoaffective disorder treated with clozapine. The D4 polymorphisms included a 13-base pair deletion, which through a frameshift leads to a truncated nonfunctional receptor protein. There were, however, no significant differences in genotype counts between responders and nonresponders. Furthermore, no side-effect was found to be associated with genetic variants of the dopamine D4 receptor.

Comparison of haptoglobin and apolipoprotein A-I on biliary lipid particles involved in cholesterol crystallization.

Several proteins are known to modulate cholesterol crystallization. We recently demonstrated that haptoglobin has cholesterol crystallization promoting activity. However, this effect is still not well understood mechanistically. The current study examined the distribution of haptoglobin compared to apolipoprotein A-I (apo A-I) to micelles, vesicles and crystals as an initial step in providing a focus for further studies of the mechanism of cholesterol crystallization activity. Specific protein purification was accomplished by immunoaffinity chromatography. The crystallization-promoting activity of biliary haptoglobin, albumin and commercial apo A-I was measured by a photometric crystal growth assay. The distribution of micelles, vesicles and proteins in model bile was determined by Sepharose CL-6B column chromatography. Detection of the presence of test proteins in cholesterol crystals was determined using specific 125I-radiolabelled proteins. Haptoglobin (20 micrograms/mL) showed a significant crystallization promoting-activity, whereas apo A-I (30 micrograms/mL) only tended to show a slight inhibitory activity. The cholesterol crystal-bound protein in each case was found to be less than 1% of the total concentration of that protein that had been added to the model bile system. The elution profile of commercial apo A-I from a Sepharose CL-6B column was strikingly altered when it was added to model bile prior to elution. In contrast, the column elution profiles for both haptoglobin and albumin were unchanged when model bile was similarly added to the sample. Haptoglobin increased the amount of cholesterol found in the vesicular fraction when compared to apo A-I. Haptoglobin does not bind tightly to either biliary lipid particles or to cholesterol crystals but does increase the amount of cholesterol in vesicles by inducing a shift from micellar cholesterol (P = 0.046). This shift appears to explain in part its promoting effect on cholesterol crystallization.

Efficacy and safety of an opiate sigma-receptor antagonist (SL 82.0715) in schizophrenic patients with negative symptoms: an open dose-range study.

The psychotomimetic effects of opiate agonists/antagonists led to the hypothesis that opiate sigma receptors could be involved in the etiology of schizophrenia. This assumption is supported by animal trials with selective sigma-receptor antagonists. SL 82.0715 is a substance with a highly selective affinity for sigma receptors. To clarify the question whether it improves negative symptoms of schizophrenia, ten chronic schizophrenic patients with a predominant negative symptomatology were examined and treated with increasing doses (2.5 - 10.0 mg/d). Psychopathology was evaluated weekly using the PANSS, BPRS, and CGI, side-effects were assessed by the HAS and the S/A scale. Four patients showed improvement of negative symptoms (two slight, two marked improvement), two patients deteriorated as regards the positive symptomatology, psychopathology in the other patients did not change. The tolerability of SL 82.0715 was very good, no extrapyramidal side-effects occurred. To further evaluate the therapeutic efficacy, open studies with a larger number of patients and/or double-blind studies are necessary.

Purification and characterization of a novel human 15 kd cholesterol crystallization inhibitor protein in bile.

Crystallization-inhibiting proteins can explain longer nucleation times associated with bile from gallstone-free subjects as compared with bile from patients with cholesterol gallstones. We partially characterized and examined the crystallization inhibitory potency of a newly purified 15 kd human biliary protein. Gallbladder bile was passed through an anti-apolipoprotein A-I (apo A-I) immunoaffinity column to extract lipid-associated proteins. The bound fraction was separated by 30 kd ultrafiltration. Sodium dodecyl sulfate-polyacrylamide gel electrophesis (SDS-PAGE) was performed under nonreducing and reducing conditions. Cholesterol crystallization activity was tested in a photometric cholesterol crystal growth assay. Isoelectric focusing was performed by using a standard gel. The purified 15 kd protein was subjected to N-terminal amino acid sequencing. Although the whole apo A-I-bound fraction contained a variety of proteins and lipids, its 30 kd filtrate yielded a nearly pure 15 kd protein with only minor contamination from apo A-1. Amino acid sequencing showed that the protein was unique. Enzymatic deglycosylation revealed no evidence for glycosylation. At a protein concentration of 10 micrograms/ml, crystallization time was delayed as compared with control and apo A-I, and final crystal mass was reduced to 75% of control. Its isoelectric point was 6.1 without isoforms. Under nonreducing conditions, the protein formed a 30 kd dimer and a 60 kd tetramer. We conclude that this protein is a novel potent biliary crystallization inhibitor protein.

Biliary alpha 1-acid glycoprotein concentrations in gallstone-free controls and in patients with multiple or solitary cholesterol gallstones.

We recently identified a promoting glycoprotein in the concanavalin A-bound fraction of gallbladder bile as a biliary form of alpha 1-glycoprotein (AAG). The concentration of biliary AAG appears to exert an important promoting effect on the speed of cholesterol nucleation in many patients with cholesterol gallstone disease. In the current study, we provide information about the biliary concentration of AAG as well as the amount and comparative potency of its subfractions in patients with and without cholesterol gallstone disease. The amount of total biliary AAG and the amounts of its different isoforms separated by concanavalin A affinity chromatography were measured by ELISA. Estimates of absolute concentrations of AAG for each sample were normalized to the sample total protein content to give relative AAG values. The promoting activity (potency) of immunopurified biliary AAG from gallstone patients and gallstone-free controls on cholesterol crystallization was compared by a crystal growth assay. The mean absolute concentration of AAG in gallstone-free controls was not significantly different from multiple stone patients. The relative concentration of AAG (micrograms per milligram total protein) was significantly increased in patients with multiple stones when compared to controls (P < 0.05), and both the absolute and relative concentrations of AAG (micrograms per milligram bile), were three- and to five fold higher in a number of these patients. The functional activity and distribution of AAG in different subfractions was similar in gallstone patients and gallstone-free controls. The relative concentration of biliary AAG is significantly greater in cholesterol gallstone patients with multiple stones than in gallstone-free controls.(ABSTRACT TRUNCATED AT 250 WORDS)