Biomedical subjects

E Schweizer

Publications and source records attributed to E Schweizer.

At least 37 records · Page 2Linked to original sources

PubMed1998

Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management.

The treatment of anxiety has evolved through various phases. Currently, there is a growing recognition that anxiety disorders are frequently chronic and/or recurrent. There is also less optimism than a decade ago that benzodiazepines will be replaced by alternative agents that are not active at the benzodiazepine receptor. Consequently, the understanding and management of benzodiazepine dependence and withdrawal continue to be of some clinical importance. This article briefly reviews the withdrawal syndrome and the pharmacological and patient variables that contribute to it. It then summarizes the various approaches to managing benzodiazepine dependence and withdrawal.

Animals↗

PubMed1998

Buspirone and imipramine for the treatment of major depression in the elderly.

BACKGROUND: The current study was designed to assess the safety and efficacy of imipramine and buspirone in the treatment of major depression in elderly depressed attendees of primary care practices. METHOD: 177 patients aged 65 and over (mean age = 72 years; range, 65-89) who met DSM-III-R criteria of unipolar major depression with a minimum Hamilton Rating Scale for Depression score of 18 were randomly assigned to 8 weeks of double-blind, placebo-controlled treatment with flexible doses of either imipramine or buspirone. RESULTS: Moderate to marked global improvement after 8 weeks of treatment (LOCF analysis) occurred in 70% of patients treated with imipramine, 61% of patients treated with buspirone, and 42% of patients treated with placebo (chi2 = 9.1, df = 2, p < .02). Drug treatment was well tolerated, with 77% of imipramine- and 61% of buspirone-treated patients completing 8 weeks of therapy. Imipramine/placebo differences were present from week 2 on, but buspirone/placebo differences occurred only at week 8. The presence of comorbid medical illness or concomitant use of nonpsychiatric prescription medications was not associated with poorer antidepressant response, increased adverse effects, or study attrition. CONCLUSION: Imipramine and to a lesser extent buspirone were found to be effective and well tolerated in the treatment of elderly depressed outpatients.

Age Factors↗

PubMed1998

The spectrum of generalised anxiety in clinical practice: the role of short-term, intermittent treatment.

BACKGROUND: DSM-IV generalised anxiety disorder (GAD) has a high lifetime prevalence, but subthreshold anxiety states are even more common, particularly in family practice. METHOD: Generalized anxiety is conceptualised as a spectrum of disorders, with transient anxiety at one end and GAD at the other. RESULTS: Based on long-term experience with family practice patients, the authors suggest that most anxious patients, wherever on this continuum they are placed, could be treated with short-term, possibly intermittent, rather than chronic anxiolytic therapy. Data are presented which show that 50% of chronic GAD patients are only in need of such short-term intermittent therapy. CONCLUSIONS: Further clinical research is needed to refine short-term, intermittent treatments for anxiety spectrum disorders, to make effective treatments available to those suffering from anxiety but falling short of diagnostic criteria for GAD, and to target more effectively the different treatment strategies.

Acute Disease↗

PubMed1997

Identification, isolation and biochemical characterization of a phosphopantetheine:protein transferase that activates the two type-I fatty acid synthases of Brevibacterium ammoniagenes.

Upon heterologous expression of the Brevibacterium ammoniagenes type-I fatty acid synthase FAS-A in Escherichia coli, only the pantetheine-free apoenzyme is synthesized. Activation of FAS-A to its holoform was achieved by transformation with a second B. ammoniagenes gene, PPT1, encoding a type-I FAS-specific phosphopantetheine transferase. PPT1 was identified as a coding sequence located immediately downstream of the second FAS gene present on the B. ammoniagenes genome, fasB. Due to this linkage, PPT1 was part of the cloned fasB DNA region and, consequently, FAS-B but not FAS-A was synthesized as holoFAS in E. coli. PPT1 encodes a protein of 153 amino acids and has a calculated molecular mass of 16,884 Da. The PPT1 gene product contains 25% identical and 42% conserved amino acids compared with the type-II acyl-carrier-protein-activating enzyme of E. coli. Although there is essentially no intergenic region between fasB and PPT1, the PPTase gene is autonomously expressed in E. coli if flanked by 200 bp of its endogenous 5' DNA. The structural independence of Ppt1p was confirmed immunologically, as specific antibodies react with the purified PPTase but not with FAS-B. Overexpression and purification of the His-tagged Ppt1p allowed the in vitro activation of apoFAS-A. This holoenzyme synthesis requires, in addition to Ppt1p, CoA and Mg2+ and leads to a specific FAS activity comparable to that of natural B. ammoniagenes FAS-A. The reactivity of the in vitro-activated FAS-A was verified by the optical FAS assay and by analysis of its in vitro products. In agreement with the known overall colinearity of B. ammoniagenes FAS-B and the Saccharomyces cerevisiae FAS1 and FAS2 gene products, a PPT1-like sequence is also observed at the C terminus of FAS2. However, in contrast to B. ammoniagenes PPT1, this sequence is an integral part of the yeast FAS2 gene. Thus, activation of type-I fatty acid synthases may be accomplished by distinct trans-acting PPTase enzymes and by intrinsic cis-acting PPTase domains.

Acyltransferases↗

PubMed1997

Heterologous expression and biochemical characterization of two functionally different type I fatty acid synthases from Brevibacterium ammoniagenes.

The coryneform bacterium, Brevibacterium ammoniagenes, contains two structurally related but functionally differentiated type I fatty acid synthases, FAS-A and FAS-B. Isolation of homogeneous preparations of both enzymes was achieved by constructing specific fasA and fasB expression systems. In B. ammoniagenes, insertional mutagenesis of fasB allowed the specific production of enzymatically active FAS-A. The corresponding fasA mutant was not suited for FAS-B purification as the level of this enzyme was extremely low, in the fasA-disruptants. Instead, FAS-B could be efficiently expressed in the heterologous host, Escherichia coli. Using specific antisera against each of the two FAS variants, FAS-A was shown to be the predominant FAS protein in B. ammoniagenes. In contrast the two enzymes are expressed at comparable rates in E. coli even though the same upstream sequences were associated with fasA and fasB, as in B. ammoniagenes. Due to their differential capacities of being activated to the phosphopantetheine-containing holo-enzyme in the heterologous host, only FAS-B but not FAS-A exhibited overall FAS activity when isolated from E. coli. Irrespective of their origin, the purified FAS-A and FAS-B proteins were indistinguishable with respect to their flavin fluorescence, their subunit size and their sucrose density gradient sedimentation characteristics. Nevertheless, the in vitro products of both enzymes differ characteristically: while FAS-A synthesizes mainly the 18-carbon fatty acids oleate and stearate with only traces of palmitate, the major product of FAS-B is palmitic acid. No unsaturated fatty acids are produced by FAS-B. Thus, the two B ammoniogenes type I fatty acid synthases differ, in spite of their very similar overall protein structure, in both their ability to synthesize oleic acid and in their chain-length specificities.

Brevibacterium↗

PubMed1997

Mitochondrial acyl carrier protein is involved in lipoic acid synthesis in Saccharomyces cerevisiae.

The yeast gene, ACP1, encoding the mitochondrial acyl carrier protein, was deleted by gene replacement. The resulting acp1-deficient mutants had only 5-10% of the wild-type lipoic acid content remaining, and exhibited a respiratory-deficient phenotype. Upon meiosis, the lipoate deficiency co-segregated with the acp1 deletion. The role of ACP1 in long-chain fatty acid synthesis was studied in fast and fas2 null mutants completely lacking cytoplasmic fatty acid synthase. When grown on odd-chain (13:0 and 15:0) fatty acids, these cells showed less than 1% of C-16 and C-18 acids in their total lipids. Mitochondrial ACP is therefore suggested to be involved with the biosynthesis of octanoate, a precursor to lipoic acid.

Acyl Carrier Protein↗

PubMed1997

Neuroanatomical substrates of late-life minor depression. A quantitative magnetic resonance imaging study.

OBJECTIVE: To examine the neuroanatomical correlates of late-life minor depression using magnetic resonance imaging. DESIGN: Cross-sectional quantitative magnetic resonance imaging study of elderly patients with minor depression and age-matched controls. SETTING: Patients and controls were recruited from the community through advertisements to the Section of Geriatric Psychiatry, University of Pennsylvania, Philadelphia. PARTICIPANTS: Our sample included 18 subjects diagnosed as having minor depression using the modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, research criteria and 31 controls without depression. Patients were free of other central nervous system disease and both groups had comparable degrees of medical comorbidity. MAIN OUTCOME MEASURES: All images were acquired on a 1.5-T scanner and absolute and normalized quantitative measures of global and focal brain and cerebrospinal fluid volumes were compared between groups. RESULTS: Prefrontal lobe volume was significantly smaller in the group with minor depression (P = .002) compared with controls after controlling for age, sex, and age by sex interactions. More global measures of brain and cerebrospinal fluid volumes were comparable in both groups. CONCLUSIONS: These data suggest that focal prefrontal atrophy may provide an important neuroanatomical substrate in late-life minor depression.

Aged↗

PubMed1997

Moclobemide in social phobia: a controlled dose-response trial.

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

Adult↗

PubMed1997

Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

This randomized, double-blind clinical trial involving 198 generalized anxiety disorder (GAD) patients was conducted to more clearly define gepirone's role for the treatment of anxiety in daily dosages of 10 to 45 mg compared with diazepam and placebo. A secondary goal was to test for possible discontinuation symptoms after abrupt discontinuation of therapy. After a 1-week washout period, patients were treated for 8 weeks and then abruptly shifted under single-blind conditions for 2 weeks on placebo. The highest attrition rate occurred with patients on gepirone (58%) and the lowest on diazepam (34%). Medication intake for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5 mg/day gepirone and was similar at week 8. The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam. Clinical improvement data showed gepirone's anxiolytic response to be delayed, being significant from placebo beginning at week 6, whereas diazepam caused significantly more relief than placebo from week 1 onward. Taper results showed that only diazepam, but not gepirone, caused a temporary worsening of anxiety symptoms or rebound.

Adult↗

PubMed1997

Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.

PURPOSE: The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways. PATIENTS AND METHODS: Pharmacokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen that included four courses of conventional-dose CP (500 mg/m2 over 1 hour every 3 weeks) followed by one final course of high-dose CP (100 mg/kg over 1 hour). Plasma concentrations of CP were analyzed by high-performance liquid chromatography (HPLC), 24-hour urinary concentrations of CP, and its inactive metabolites (carboxyphosphamide, dechloroethylcyclophosphamide [dechlorethylCP], ketocyclophosphamide [ketoCP]) were determined by 31-phosphorus-nuclear magnetic resonance (31P-NMR)-spectroscopy. RESULTS: There was no difference in dose-corrected area under the concentration-time curve (AUC) (216 v 223 [mumol.h/[mL.g]), elimination half-life (4.8 v 4.8 hours), systemic clearance (79 v 77 mL/min) and volume of distribution (0.49 v 0.45 L/kg) of CP between conventional- and high-dose therapy, respectively. However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min). Consequently, metabolic clearance to the remaining (reactive) metabolites decreased from 52 to 38 mL/min (P < .001). The relative contribution of the different elimination pathways to overall clearance of CP demonstrated wide interindividual variability. CONCLUSION: Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift in the relative contribution of different clearances to systemic CP clearance in favor of inactivating elimination pathways, thereby indicating saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition.

Adult↗

PubMed1997

Venlafaxine:a novel antidepressant compound.

Venlafaxine is a new antidepressant that inhibits the reuptake of both 5-hydroxytryptamine (serotonin; 5-HT) and noradrenaline (NA). It is somewhat more potent as an inhibitor of the reuptake of 5-HT than NA. Its potency to inhibit the reuptake of 5-HT is comparable to that of tricyclic antidepressants (TCAs) such as amitriptyline or imipramine, but it is less potent than these drugs at inhibiting the reuptake of NA. Consequently, at low doses, venlafaxine may be a more effective inhibitor of the reuptake of 5-HT than that of NA. The major metabolite of venlafaxine in humans, O-desmethylvenlafaxine, has comparable potency to the parent drug for inhibiting the reuptake of either NA or 5-HT in vitro, but it is less potent in vivo. Both venlafaxine and O-desmethylvenlafaxine are essentially devoid of activity at muscarinic cholinergic, H1 histaminergic, and 1-adrenoceptors. This probably accounts for venlafaxine having a side-effect profile similar to that of selective serotonin reuptake inhibitors (SSRIs) rather than that of TCAs. Venlafaxine is subject to extensive first-pass metabolism and is metabolised by the cytochrome P450 isoenzyme IID6 in the liver. The half-life of venlafaxine is 3-4 h and that of its principal metabolite is about 10 h. The daily dose of venlafaxine can be administered as either two or three divided doses without altering significantly the pharmacokinetics of venlafaxine. The most common side-effects of venlafaxine are nausea, sedation, dizziness, dry mouth and sweating, as well as sexual dysfunctions, primarily problems with erection and delayed ejaculation. In some patients, venlafaxine also causes sustained elevations in both systolic and diastolic blood pressure; this effect is dose-dependent. Venlafaxine is much safer in overdosage than the TCAs. Antidepressant efficacy of venlafaxine has been found both in out-patients and in-patients. In general, its efficacy is comparable to that of comparator drugs (primarily TCAs or SSRIs), and in some cases even greater, and its efficacy is greater than that measured with placebo.

Journal Article↗

PubMed1997

Strategies for treatment of generalized anxiety in the primary care setting.

Generalized Anxiety Disorder (GAD) is a highly prevalent condition whose course of illness is often chronic in nature and fluctuating in severity. Pharmacotherapy options include the benzodiazepines, the azapirones, of which only buspirone is marketed at the present time, and the antidepressant imipramine. Buspirone is probably the treatment of choice when prolonged therapy is indicated because it does not produce physical dependence, dose not interact with alcohol, and does not cause psychomotor impairment. Dosing instructions for buspirone and guidelines for switching patients from benzodiazepines to buspirone are offered. Non-drug therapies such as interpersonal and cognitive therapies are often also found helpful in treating patients with GAD.

Anxiety Disorders↗

PubMed1997

The clinical presentation of generalized anxiety in primary-care settings: practical concepts of classification and management.

On the basis of our long-term experience in treating family-practice patients and conducting clinical research with them, we propose a practical clinical nosology that takes into account the subsyndromal spectrum of generalized anxiety, as well as patterns of illness, particularly for the family-practice setting. We present an alternative proposal of how to conceptualize generalized anxiety disorders clinically into acute anxiety, subacute anxiety, chronic anxiety, and double anxiety. This is followed by a discussion of the implications for choosing from among the various anxiolytic treatment options available to the family physician and of the importance of the therapeutic context in which treatment is provided. Anxiolytics are not a panacea, but only tools to allow the patient to help himself or herself. Irrespective of which anxiolytic is chosen, and irrespective of the chronicity of the anxiety, short-term (2 to 6 weeks) anxiolytic therapy--if necessary provided more than once on an intermittent basis--should be the treatment approach of first choice. Data are presented to suggest that 50% of all chronically ill patients who have generalized anxiety disorder could benefit from such a treatment approach.

Anti-Anxiety Agents↗

PubMed1997

Placebo response in generalized anxiety: its effect on the outcome of clinical trials.

The development of new treatments for generalized anxiety disorder increasingly has been sabotaged by a high placebo-response rate. As a consequence, and in contrast to the surge of approvals for new antidepressants, only one new anxiolytic has been approved by the U.S. Food and Drug Administration in the past 15 years. This article presents a brief review of factors that contribute to the placebo response in treatment studies of generalized anxiety. Since anxiety is a normal emotion that is sensitive to a variety of life stresses, it is particularly difficult to achieve the primary goal of a clinical trial, which is to extract the "signal" of a drug effect from the "noise" of background fluctuations in symptoms. Data from the published literature and from the authors' research unit concerning placebo-response trends are reviewed.

Anti-Anxiety Agents↗

PubMed1996

Zalospirone in major depression: a placebo-controlled multicenter study.

Compounds active at the serotonin (5-HT)1A receptor (mostly azapirones) have shown some evidence of antidepressant effect. We report here the results of an antidepressant trial with zalospirone, a novel cyclic imide with 5-HT1A partial agonist activity. Two hundred eighty-seven outpatients (mean age 44 years, 55% men, 45% nonfertile women) who met criteria for unipolar major depression with a minimum 21-item Hamilton Rating Scale for Depression (HAM-D) score of 20 were randomly assigned to receive 6 weeks of double-blind treatment with either placebo or one of three fixed doses of zalospirone (6, 15, or 45 mg/day), administered three times daily. The high dose (45 mg) of zalospirone produced a significant antidepressant effect compared with placebo from week 2 on with mean improvement (change from baseline) in HAM-D total score of 12.8 versus 8.4 (p < 0.05) at week 6. Clinical improvement with the high dose of zalospirone was consistent across all outcome measures, however, only in the observed cases and not the last-observation-carried-forward analyses. Improvement with the 6-mg or 15-mg doses was greater than that with placebo, but not significantly so, suggesting a dose-response effect. Although the 45-mg dose of zalospirone seemed to have significant antidepressant efficacy, it was not well tolerated. Dizziness and nausea were noted in almost half of the patients, and by week six, 51% of patients in the high-dose group had dropped out. Whether or not tolerance to this high dose might be improved by gradual drug titration, only future research can answer.

Adult↗

PubMed1996

Identification and functional differentiation of two type I fatty acid synthases in Brevibacterium ammoniagenes.

The fatty acid synthase (FAS) from Brevibacterium ammoniagenes is a homohexameric multienzyme complex that catalyzes the synthesis of both saturated and unsaturated fatty acids. By immunological screening of a B. ammoniagenes expression library, an fas DNA fragment was isolated and subsequently used to clone the entire gene together with its flanking sequences. Within 10,525 bp of sequenced DNA, the 9,189-bp FAS coding region was identified, corresponding to a protein of 3,063 amino acids with a molecular mass of 324,910 Da. This gene (fasA) encodes, at its 5' end, the same amino acid sequence as is observed with purified B. ammoniagenes FAS. A second reading frame encoding another B. ammoniagenes FAS variant (FasB) had been identified previously. Both sequences are colinear and exhibit 61 and 47% identity at the DNA and protein levels, respectively. By using specific antibodies raised against a unique peptide sequence of FasB, this enzyme was shown to represent only 5 to 10% of the cellular FAS protein. Insertional inactivation of the FasB coding sequence causes no defective phenotype, while fasA disruptants require oleic acid for growth. Correspondingly, oleate-dependent B. ammoniagenes cells obtained by ethyl methanesulfonate mutagenesis were complemented by transformation with fasA DNA but not with fasB DNA. The data indicate that B. ammoniagenes contains two related though differently expressed type I FASs. FasA represents the bulk of cellular FAS protein and catalyzes the synthesis of both saturated and unsaturated fatty acids, while the minor variant, FasB, cannot catalyze the synthesis of oleic acid.

Adhesins, Escherichia coli↗

PubMed1996

Occurrence of polychlorinated terphenyls (PCTs) in indoor particulate matter.

In the course of a routine investigation concerned with polychlorinated biphenyl (PCB) contamination of dust collected in classrooms of a junior high school, a group of electron capture detector (ECD)-sensitive compounds with high boiling points were found in addition to PCBs. Using gas chromatographic-mass spectrometric techniques, these compounds were identified as polychlorinated terphenyls (PCTs). Additional measurements indicated that the PCTs were present only in particulate matter collected from the tops of fluorescent light frames but not in air samples obtained concomitantly in the classrooms. Attempts to identify the PCT emission source were unsuccessful. A survey of the literature revealed that PCTs are ubiquitously distributed environmental contaminants, although no data on their indoor occurrence have been reported to date. In view of the toxic effects of PCTs, which seem to be as important as those of PCBs, further attention should be given to the possible presence of PCTs in indoor environments.

Air Pollutants↗

PubMed1996

An open-label trial of nefazodone in high comorbidity panic disorder.

BACKGROUND: Nefazodone is a recently marketed compound with demonstrated efficacy in major depression. This study was undertaken to assess the efficacy and safety of nefazodone in a sample of panic disorder patients with a high degree of depressive comorbidity. METHOD: Fourteen patients were screened for entry into an open 8-week trial of nefazodone clinically titrated between 200-600 mg. Patients fulfilled DSM-III-R criteria for panic disorder and were allowed to enter with concurrent diagnoses of major depression, dysthymia, generalized anxiety disorder, and depression NOS. Primary outcome measures included panic attack frequency and severity and the Clinical Global Impression scale. RESULTS: At Week 8 of treatment, 10/14 patients (71%) were judged to be much or very much improved with study treatment. Panic attack frequency decreased from a mean of 5.4 at baseline to 2.1 at Week 8, reaching significance by Week 8 (p < .05) as did decreases in phobic anxiety. Improvement in panic attack severity, phobic avoidance, HAM-D, HAM-A, CGI-Severity, and Sheehan Disability Scale scores was significant by Week 4. Five of the 8 patients with comorbid major depression were responders, as were 3/5 patients with generalized anxiety disorder comorbidity. Five of 6 patients with pure panic or minor depressive symptoms responded to the study treatment. None of the patients withdrew because of side effects of nefazodone. CONCLUSION: This report presents preliminary evidence for the efficacy and tolerability of nefazodone in panic disorder and panic with comorbid depression or depressive symptoms.

Adult↗