[Premature interpretation of prescription data can be erroneous. Pharmacoepidemiology--chance and risk].
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Drug Therapy↗
Biomedical subjects
M Linden
Publications and source records attributed to M Linden.
Interactions between brain mitochondria and cytoskeleton: evidence for specialized outer membrane domains involved in the association of cytoskeleton-associated proteins to mitochondria in situ and in vitro.
The surface distribution of several proteins (porin, hexokinase, and two proteins associated with microtubules or actin filaments) on the outer membrane of brain mitochondria was analyzed by immunogold labelling of purified mitochondria in vitro. The results suggest the existence of specialized domains for the distribution of porin in the outer mitochondrial membrane. Similarities between the distribution of porin and the distribution of microtubule-associated proteins bound in vitro to mitochondria suggested that mitochondria and microtubules interact by binding microtubule-associated proteins to porin-containing domains of the outer membrane. This hypothesis was supported by biochemical studies on outer mitochondrial proteins involved in in vitro binding of cytoskeleton elements. In vitro interactions between mitochondria and microtubules or neurofilaments were analyzed by electron microscopy. These studies revealed cross-bridging between the outer membrane of mitochondria and the two cytoskeleton elements. Cross-bridging was influenced by ATP hydrolysis and by several proteins associated with the surface of mitochondria or with microtubules. In addition, unidentified proteins which were recognized by antibodies to all intermediate filaments subunits were associated either with the mitochondrial surface or with microtubules. This data suggest the participation of additional cytoplasmic proteins in the interactions between cytoskeleton elements and mitochondria.
Animals↗
Effects of a corticosteroid, budesonide, on alveolar macrophage and blood monocyte secretion of cytokines: differential sensitivity of GM-CSF, IL-1 beta, and IL-6.
Down-regulation of cytokine production in activated human blood monocytes (BMs) and alveolar macrophages (AMs) can be achieved in vitro by treatment with corticosteroids. The inhibition of cytokine secretion by corticosteroids may have important therapeutic consequences in e.g. asthma. However, relatively little is known about possible differences in the sensitivity of different cytokines to corticosteroid treatment. Homologous BMs and AMs were obtained from six healthy volunteers. Secretion of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the cultures of lipopolysaccharide (LPS) stimulated adherent BMs and AMs was analysed using specific immunoassays. Sensitivity of the IL-1 beta, IL-6, and GM-CSF secretion to the in vitro treatment with a synthetic corticosteroid, budesonide, was compared. BMs and AMs displayed significant differences in both cytokine secretion and susceptibility to regulation by budesonide. When added to the BM cultures concomitantly with LPS, budesonide suppressed IL-1 beta and IL-6 only partially (to 30% of the control level). In contrast, GM-CSF release in these cultures was almost totally inhibited by budesonide (> or = 10(-8) M). The IC50 for inhibition of the GM-CSF secretion was as low as 2 x 10(-10) M. In the AM cultures, budesonide had very little effect on IL-1 beta and IL-6 secretion (inhibition to 80% and 60% of control levels, respectively), while GM-CSF secretion was suppressed to 20% of control by budesonide concentrations > or = 10(-7) M.(ABSTRACT TRUNCATED AT 250 WORDS)
Budesonide↗
Basophil and eosinophil differentiation in allergic reactions.
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Animals↗
Antioxidant activity of some diarylselenides in biological systems.
The selenoorganic compounds di(4-aminophenyl)selenide (10) and 4-nitro-4'-amino-diphenylselenide (36) were shown to inhibit lipid peroxidation in ADP/Fe2+/ascorbate-treated microsomes and tert-butylhydroperoxide-treated hepatocytes with IC50s of 3 and 10 microM, and 14 and 10 microM, respectively. In the former system, these inhibition constants compare favourably with those of Ebselen and classical antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In the cell system, these selenium compounds were equipotent with BHA but more potent than Ebselen and its analogues. The diamino compound (10) was also an effective inhibitor of lipid peroxidation initiated by diquat redox cycling in hepatocytes, again being equipotent with BHA but more potent than Ebselen and its analogues, which actually stimulated lipid peroxidation in this test system. Manipulation of the amino functions of (10) and (36) by alkylation or acylation altered the antioxidant capacity. Optimal activity in this series was achieved by N-ethylation or N-isobutylation of (10). This produced antioxidants having IC50s below 1 microM in the microsome system, 3-13 microM in the tert-butylhydroperoxide system, and being 100% effective in the diquat model at 50 microM. On the other hand, acylation or alkylation of the amino groups with long chain acyl or alkyl groups reduced the efficacy of the structures below that of the parent diamine. As with other antioxidant compounds, several of the chalcogenides were relatively selective inhibitors of monocyte 5'-lipoxygenase-dependent secretion of LTB4 as compared to their effect on cyclooxygenase-dependent secretion of PGE2 (for example compound 42 had IC50s of 0.6 microM and 10 microM, respectively). No correlation was observed between the redox-properties of the chalcogenides and their respective abilities to inhibit these enzymes.
Adenosine Diphosphate↗
Therapeutic standards in psychopharmacology and medical decision-making.
Treatment surveys regularly show deviations of routine treatment from treatment guidelines. An analysis of the scientific basis of classical treatment standards, as derived from controlled treatment trials, shows that they do not take into account many variables with major impact on routine treatment. A better theoretical framework for understanding medical decision-making under complex stimulus conditions is provided by action theory. Studies that test treatment strategies instead of treatments and field observational studies, for both of which examples are given, are necessary adjuncts to controlled clinical trials in the quest for more scientifically based treatment guidelines.
Decision Making↗
Structure and feasibility of a standardized stepwise drug treatment regimen (SSTR) for depressed inpatients.
"Standardized stepwise treatment regimes" (SSTR) are one way to rationally guide treatment in cases where the first treatment intervention did not yield satisfactory results. At the Department of Psychiatry of the Free University of Berlin a SSTR has been implemented into routine drug treatment for depressive disorders. The SSTR consists of eight consecutive treatment steps. If there is no sufficient change in the Bech-Rafaelsen Melancholy Scale (< 25% score reduction) in the course of two weeks, treatment has to progress to the next step. This paper describes the overall feasibility and efficacy of the strategy and the progress of the patients within the SSTR. Of those who enter the "antidepressant monotherapy phase" 52% finish treatment successfully at this stage or during the following "lithium augmentation phase". The results of this treatment-monitoring study also show that during consecutive phases of the SSTR a considerable proportion of patients in a university inpatient setting had their treatment modified according to special attitudes and clinical experiences of physicians and patients. The reasons for deviating from the SSTR obviously were more convincing than the rationale for progressing to the next step. SSTR, therefore are an important tool to give complex treatment courses a rational basis, even in patients where clinical case management requires deviations from the outlined sequence of treatment steps.
Antidepressive Agents↗
Clinical recognition and drug treatment of depression in cases found by standardized assessment.
The determination of need of care is an important problem for public health. In an epidemiological perspective the question is whether the right people get the right treatment. The answer depends on a variety of methodological issues such as case-definition, case-identification, sampling, and treatment assessment. Case-definition is done by patients themselves and by experts such as physicians or scientists. This study compares the clinical approach of family physicians with the standardized approach of epidemiologists. In two epidemiological studies, the Berlin Aging Study (BASE) and the WHO Study on Psychological Problems in General Health Care (WHO/PPGHC), diagnosis and treatment of major depression in the field were analyzed. In spite of different methods, both studies showed a high rate of unrecognized major depressions as defined by DSM-III-R criteria. This lack of case-recognition by the primary care physicians corresponds to the fact that less than then percent of these patients were treated with antidepressants and none of them had been seen by a psychiatrist. The question to be discussed is whether these results speak for an underrecognition of cases that are in need of care under clinical conditions or an inflation of the respective numbers by standardized methods.
Aged↗
Seasonal variation in the function of blood monocytes obtained from healthy nonsmokers, asymptomatic smokers, and smokers with chronic bronchitis.
The present study focused on two questions: What effects do cigarette smoking and chronic bronchitis have on the function of the precursors of alveolar macrophages, the blood monocytes? Can seasonal variations affect the function of these cells? Phagocytic activity (the proportion of yeast-ingesting cells and the mean number of yeast particles per ingesting cell) and metabolism of arachidonic acid [secretion of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in zymosan-stimulated cultures] were studied as markers of monocyte function during three seasons: spring (May-June), autumn (November-December), and winter (February). Smokers with chronic bronchitis (SCBs) and asymptomatic smokers (ASs) had a lower proportion (p < 0.05) of ingesting monocytes than healthy nonsmokers (HNSs) during spring, but not during the other two seasons. The secretion of PGE2 was highest during autumn and lowest during spring in the monocytes of all three groups. In autumn, LTB4 secretion was increased in the monocytes of HNSs (p < 0.05) but not in those of ASs and SCBs. LTB4 secretion was similar in all groups during the other two seasons. Cigarette smoking and chronic bronchitis seem to impair the function of monocytes and may thereby affect the systemic host defense activity. Cells collected during autumn were generally more active than those sampled in spring, indicating marked seasonal variation in the function of monocytes from all three groups.
Arachidonic Acid↗
[Guidelines for carrying out application studies in psychopharmacotherapy. "Phase IV Research" Study Group of the Society of Neuropsychopharmacology and Pharmacopsychiatry].
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Clinical Trials, Phase IV as Topic↗
Aspirin effect on early and late changes in acute lung injury in sheep.
OBJECTIVE: There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B2 (TxB2) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep. DESIGN: 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i.v.) 30 min before OA, the others saline as placebo. MEASUREMENTS AND RESULTS: Pulmonary and tissue gas exchange, pulmonary and systematic hemodynamics, respiratory system mechanics, TxB2 and 6-keto-PGF1 alpha, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB2 generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at approximately 1 in ASA-group compared to its fall to approximately 0.7 in controls. CONCLUSION: Our findings suggest that ASA: 1) is only effective to treat the very transient TxB2-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB2; 2) has a transient protective effect on the TxB2-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO2.
6-Ketoprostaglandin F1 alpha↗
Therapist individuality in the diagnosis and treatment of depression.
The influence of physician variables on the diagnosis and treatment of depression was analysed by presenting a trained pseudo-patient to four physicians each with different professional backgrounds. Although all physicians had earlier given their informed consent to the study design, they thought that they were treating a real patient during regular practice hours. All physicians assessed the acute psychopathology almost completely except for suicidal thoughts. Despite similar information about the case, four different diagnoses/pathogenetic concepts and four different treatments were chosen. Medical decision processes and their results can be related to the professional background and personal attitudes of physicians.
Adult↗
Benzodiazepines in medical teaching. A survey of university departments of pharmacology, psychiatry, and internal medicine in Germany.
Benzodiazepines are one of the most frequently prescribed classes of medications and by far the biggest class of psychotropic drugs. For years they have been under critical discussion both professionally and in public. The questions arise as to what view is held by university teachers on this topic and how much attention is given to benzodiazepines and benzodiazepine-related problems. Have there been changes in medical teaching in recent years? All the West German departments of psychiatry, internal medicine, and pharmacology were asked by means of a mailed questionnaire to report on their teaching practice. 84.8% of the questionnaires were returned. Results show that mainly psychiatrists and pharmacologists place special emphasis on benzodiazepines in medical teaching. Additionally, in recent years they have devoted more time to this drug class and to related risks in particular. In particular, psychiatrists deal more with benzodiazepines in postgraduate training and the further training of physicians as well as in their scientific research. When the responses of university teachers in psychiatry, internal medicine and pharmacology are summed up, they show that chiefly psychiatrists have responded in their teaching to the current discussion. This contrasts particularly with internists. This has to be discussed in the light of the fact that, in terms of quantity, minor tranquilizers are predominantly prescribed by nonpsychiatrists.
Benzodiazepines↗
Drug monitoring study (phase IV) of xantinolnicotinate (Complamin) in general practice.
For 30 years, xantinolnicotinate has been on the market for the treatment of impaired brain function, i.e., organic brain syndromes of various etiologies. Controlled double-blind phase-III clinical trials have shown that xantinol-nicotinate is an effective drug in the treatment of dementia. Nevertheless, it is also important to assess xantinolnicotinate under routine treatment conditions in order to learn what type of patient is preferably treated, which ADRs can be observed how often, and whether the efficacy claimed by phase III studies can still be seen under routine treatment conditions. Theoretically, the more complex treatment situation in routine practice could lead to major changes in the selection of patients, the type and frequency of ADRs, or efficacy. The treatment of 10,134 patients was monitored in a treatment observation study. Results show that target illnesses are not cases of 'pure dementia', but more complex cases, in which multimorbidity plays an important role, so that the older term 'cerebrovascular insufficiency' seems more appropriate to describe this group of patients. Another interesting group is made up of younger patients suffering from a variety of psycho-organic syndromes. The assessment of therapeutic efficacy, e.g., with the SCAG, shows highly significant improvements during treatment, which are well comparable to those reported in controlled studies. The success of treatment was most expressed in the target symptoms "dizziness", "fatigue", "disturbance of concentration", "affective disorders", and "disturbance of vigilance and vitality". In 87% of these cases, no adverse drug reactions were reported.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Benzodiazepine substitution in medical practice. Analysis of pharmacoepidemiologic data based on expert interviews.
Pharmacoepidemiologic data have shown a consistent reduction in benzodiazepine (BZ) prescriptions over the past decade. The question remains as to whether BZs are simply put aside or whether other medications are used as substitutes. Expert interviews, at which a stratified sample of 114 psychiatrists, internists, and general practitioners were presented with case studies, were conducted to learn about the therapeutic alternatives in the field of benzodiazepine-related indications administered in daily practice. These results were used to analyze trends in pharmacoepidemiologic prescription data for all patients under the general health insurance plan from 1981 to 1988. The experts identified distinct alternatives to BZs in different clinical situations, including neuroleptics, antidepressants, phototherapeutics, and analgesics. When these findings were transferred to pharmacoepidemiologic data, results revealed an increase in the prescription of alternative medications that apparently compensated for reduced BZ use. Overall there was no change (or, rather, no increase) in the total of psychotropic prescriptions during the period of reduced BZ prescriptions. Our findings indicate that reduction in benzodiazepines prescription is associated with substitution by various other psychotropic drugs. This has positive as well as negative consequences, and there must be discussed in detail before sound recommendations can be given as to which type of drug. BZs included, is the best choice in which type of illness.
Adult↗
Three types of early termination of antidepressant drug treatment.
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Depressive Disorder↗
Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis.
To assess the manifestation and location of airway inflammation in smokers with chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD), we lavaged the airways of 12 smokers with CB and 11 smokers with COPD and coexisting CB (OCB). For comparison, the airways of 5 asymptomatic smokers (AS) and 10 healthy nonsmokers (HNS) were lavaged. In all cases, the first lavage aliquot, labeled "bronchial lavage" (BL), was processed separately from the four subsequent aliquots, which were combined and labeled "bronchoalveolar lavage" (BAL). The composition of BL and BAL fluids indicate an ongoing inflammatory process in the airways of all three groups of smokers. CB patients with obstruction had significantly lower concentrations of inflammatory cells in the BL and BAL fluids compared with subjects with nonobstructed CB. Furthermore, airway obstruction, indicated by a reduced FEV1, was significantly correlated with the concentrations of glutathione (p < 0.001), myeloperoxidase (MPO; p < 0.01), and eosinophil cationic protein (ECP; p < 0.01) in BAL fluids. Taken together, these findings suggest that the manifestations of inflammation present in the airways of smokers with CB are different in those who have developed obstruction compared with those who have not.
Adult↗
Early neuroleptic intervention in schizophrenia: are prodromal symptoms valid predictors of relapse?
All recently completed controlled two-year studies on intermittent, early neuroleptic intervention treatment have failed to compare favourably with studies on maintenance treatment concerning relapse prevention. The reason for this failure is still unclear. Therefore the implicit, but as yet unproven, hypothesis that a relapse can be predicted from prodromal symptoms was tested from the perspective of our German multicentre study. Results demonstrate that this is not the case. Possible reasons for and clinical implications of this negative finding are discussed.
Adult↗