[A retrospective mortality analysis of natural deaths of the 65+ generation based on postmortem autopsies performed at the Institute of Legal Medicine in Frankfurt am Main during two periods]. / Retrospektive Mortalitätsstudie natürlicher Todesfälle der Generation 65+ im Obduktionsgut der Rechtsmedizin Frankfurt am Main anhand zweier Zeitintervalle.

BACKGROUND AND AIM OF THE STUDY: In Germany, a constant demographic change is taking place, which leads to an increasing aging of the society. The present study aimed to analyze natural deaths occurring at an age of ≥ 65 years, since health vulnerability in this age group is gaining importance. MATERIAL AND METHODS: Autopsy reports of the Institute of Forensic Medicine, University Hospital of the Goethe University Frankfurt/Main, Germany, were retrospectively evaluated regarding natural death cases of ≥ 65-year-olds in a time comparison (period I: 2000-2002; period II: 2013-2015). RESULTS: During both periods, a total of 1206 autopsies concerning this age group were performed. Among these, 404 cases (33.5%) of unnatural death and 39 cases (3.2%) of a combination of natural and unnatural death were recorded; in 94 cases (7.8%), the manner of death could not be elucidated. The majority (n = 669; 55.5%) included cases of natural death. In the largest group of these (n = 350; 52.3%), cardiac causes of death were predominant, followed by 132 (19.7%) respiratory and 47 (7.0%) abdominal causes of death. In addition, 37 (5.5%) cases of malignant neoplasms, 33 (4.9%) of ruptures of large vessels, 33 (4.9%) of cerebral, and 37 (5.5%) other cases of natural death were noted. A significant decrease of cardiac causes of death was observed in the comparison of periods I and II. In particular, there was a significant decrease in high-grade occlusive coronary sclerosis. Moreover, there were significant differences between both sexes. Men had significantly more bypasses, stents and heart scars and suffered a myocardial infarction about 10 years earlier than women. CONCLUSION: The results of the present study are largely consistent with the literature. The decrease in numbers of cardiac deaths may be attributed to increasingly better medical care and to a significantly higher rate of stent implantation. Especially in times of pandemics, the role of forensic gerontology will become more important.

[Tryptophan immunoadsorption for multiple sclerosis and neuromyelitis optica: therapy option for acute relapses during pregnancy and breastfeeding]. / Tryptophan-Immunadsorption bei Multipler Sklerose und Neuromyelitis optica : Therapieoption bei akuten Schüben in der Schwangerschaft und Stillphase.

BACKGROUND: Approximately 25 % of women with multiple sclerosis (MS) suffer clinically relevant relapses during pregnancy. Almost all disease-modifying drugs are contraindicated in pregnancy. High-dose glucocorticoids have some serious risks, especially within the first trimester. Tryptophan immunoadsorption (IA) provides a safe option to treat MS relapses during pregnancy. OBJECTIVES: In this case series we describe for the first time the use of tryptophan IA for MS and neuromyelitis optica (NMO) relapses during pregnancy and breastfeeding. PATIENTS AND METHODS: In this study a total of 9 patients were retrospectively analyzed of which 7 patients received IA treatment during pregnancy, 2 during breastfeeding and 4-6 tryptophan IA treatments were performed per patient with the single use tryptophan adsorber. Primary outcome was symptom improvement of the relapse. RESULTS: In this study four patients with MS and one with NMO relapse during pregnancy were treated with IA without preceding glucocorticoid pulse therapy. The MS patients showed improvement in the expanded disability status scale (EDSS) by at least one point, the NMO patient showed significant improvement in visual acuity and two pregnant patients with steroid-refractory relapses showed clinically relevant improvement after IA. Of the patients two suffered from steroid-refractory relapses during breastfeeding and relapse symptoms improved in both cases after treatment with IA. All treatments were well tolerated and no serious adverse events occurred. CONCLUSION: Tryptophan IA was found to be safe, well-tolerated and effective in the treatment of MS and NMO relapses during pregnancy and breastfeeding, sometimes without preceding glucocorticoid pulse therapy. A binding recommendation is limited without prospective clinical studies.

Tryptophan immunoadsorption for the treatment of autoimmune encephalitis.

BACKGROUND AND PURPOSE: Detection of autoantibodies against neuronal surface antigens and their correlation with the pattern and severity of symptoms led to the definition of new autoimmune-mediated forms of encephalitis and was essential for the initiation of immunotherapies including plasma exchange. The elimination of autoantibodies using selective immunoadsorption (IA) is a pathophysiologically guided therapeutic approach but has not yet been evaluated in a separate analysis. METHODS: A retrospective analysis was performed of patients with autoimmune encephalitis who were treated with tryptophan IA in six neurological clinics between 2009 and 2013. The modified Rankin scale (mRS) was used to evaluate neurological status before and after IA. RESULTS: Data on 13 patients were documented. Twelve patients were positive for specific autoantibodies (NMDA-R, GABA, GAD, Lgl1). Patients received a series of a median of six IA treatments. Median mRS of all patients was 3.0 before IA and 2.0 after IA (P < 0.001). Eleven patients improved by at least one point in mRS after IA. CONCLUSION: For autoimmune-mediated forms of encephalitis rapid elimination of autoantibodies with selective IA seems to be an effective therapeutic option as part of multimodal immune therapy.

[Therapeutic apheresis for autoimmune encephalitis: a nationwide data collection]. / Therapeutische Apherese bei autoimmuner Enzephalitis: Eine bundesweite Datenerhebung.

BACKGROUND: The correlation between detection of autoantibodies and the pattern and severity of symptoms in patients with encephalitis was the crucial factor for the initiation of immune therapy. The elimination of autoantibodies using therapeutic apheresis by plasma exchange (PE) and immunoadsorption (IA) is a pathophysiologically guided therapeutic approach. The aim was to evaluate the current use of PE and for the first time also of IA for patients with autoimmune encephalitis. METHODS: A nationwide data collection was performed and the modified Rankin score (mRS) was used to evaluate the severity of neurological symptoms. RESULTS: Data of 31 treatment courses (30 patients and 1 relapse) were documented and 22 patients were positive for autoantibodies (NMDA-R, GABA, VGKC, Hu). In 23 cases PA was performed, tryptophan IA in 7 cases and in 1 patient both methods were applied. In 67 % of the treatment courses the mRS improved and the mean mRS of all patients was 3.2 before apheresis and 2.2 after apheresis (p < 0.05). All patients who were treated with IA improved clinically from a mean mRS of 3.9 before IA to 1.9 after IA (p < 0.01). CONCLUSIONS: For immune-mediated forms of encephalitis rapid elimination of autoantibodies with PA and IA seems to be an effective therapeutic option as part of a multimodal immune therapy and is already established in many clinics in Germany.

[Immunoadsorption for steroid-unresponsive multiple sclerosis-relapses: clinical data of 14 patients]. / Immunadsorption bei steroidrefraktärem Schub der Multiplen Sklerose : Klinische Erfahrungen bei 14 Patienten.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating immune-mediated disease of the central nervous system, often associated with relapses. Plasma exchange (PE) has become established as an escalation therapy for steroid-unresponsive relapses in national and international guidelines. PE is a non-selective apheresis method with elimination of the entire plasma with subsequent substitution. Selective extracorporeal elimination of autoantibodies and immune complexes with immunoadsorption (IA) is increasingly replacing PE for the treatment of autoimmune neurological diseases due to its equivalent efficacy and advantageous safety profile. The use of IA for MS still remains to become established. The aim of this retrospective investigation was to evaluate efficacy and safety of IA in patients with steroid-unresponsive relapses. PATIENTS AND METHODS: Fourteen patients with steroid-unresponsive MS relapses were retrospectively analysed. Patients received six IA treatments within 2 weeks using the single-use tryptophan adsorber. Peripheral venous access was used in 11 patients, and 3 patients needed a central line. The plasma volume treated was 2 l per IA. Efficacy criteria were improvement in symptoms of MS relapses which were measured with the Kurtzke scale (EDSS, FS) and visual acuity measurements for patients with optic neuritis. RESULTS: In 12 of 14 patients the major symptom of MS relapse improved to a clinically relevant extent after tryptophan IA; no patient got worse, corresponding to a response rate of 86%. Mean EDSS and FS in patients with spastic paresis (n=4) and dizziness (n=2) as well as mean visual acuity in patients with optic neuritis (n=8) significantly improved after IA. IA treatments were safe, with good tolerability, and no severe adverse events occurred. CONCLUSION: Immunoadsorption for the treatment of steroid-unresponsive MS relapses was safe and effective. The response rate was comparable to published results with PE. With IA, in contrast to unselective PE, administration of human plasma products is not necessary, avoiding associated risks.

A topography of executive functions and their interactions revealed by functional magnetic resonance imaging.

We used fMRI to study the brain processes involved in the executive control of behavior. The Sustained Attention to Response Task (SART), which allows unpredictable and predictable NOGO events to be contrasted, was imaged using a mixed (block and event-related) fMRI design to examine tonic and phasic processes involved in response inhibition, error detection, conflict monitoring and sustained attention. A network of regions, including right ventral prefrontal cortex (PFC), left dorsolateral PFC (DLPFC) and right inferior parietal cortex, was activated for successful unpredictable inhibitions, while rostral anterior cingulate was implicated in error processing and the pre-SMA in conflict monitoring. Furthermore, the pattern of correlations between left dorsolateral PFC, implicated in task-set maintenance, and the pre-SMA were indicative of a tight coupling between prefrontally mediated control and conflict levels monitored more posteriorly. The results reveal that the executive control of behavior can be separated into distinct functions performed by discrete cortical regions.

[Rheophoresis. A systematic approach to therapy of age-related macular degeneration (AMD)?]. / Rheopherese Ein systemischer Therapieansatz für die altersabhängige Makuladegeneration (AMD)?

BACKGROUND: Choroidal microcirculation is impaired in age-related macular degeneration (AMD), and leads to deposition of lipids and proteins in Bruch's membrane. Rheophoresis can improve choroidal microcirculation by eliminating high molecular weight, rheologically relevant plasma proteins. The objective of this post-certification study was to analyse the effect of rheophoresis in 10 AMD patients. PATIENTS AND METHODS: A total of 6 patients with early AMD and 4 with late AMD in one eye (initial visual acuity equivalent 0.2-0.8) received rheophoresis treatment 10 times over an 18-week period. Visual acuity and color vision were determined initially and after 3, 5 and 12 months and fluorescein angiography was performed. RESULTS: Patients with early AMD showed improvement of visual acuity (2 lines on ETDRS charts) in 2 out of 6 cases and a stable visual acuity in 4 out of 6 cases 1 year after rheophoresis, whereas patients with late AMD showed improvement of visual acuity (2 lines on ETDRS charts) in 1 out of 4 cases and a stable visual acuity in 3 out of 4 cases. In red-free fundus photography, a reduction in drusen size and number could be observed in 4 out of 10 cases. CONCLUSION: The results of this investigation seem to be in accordance with data from previously published controlled clinical trials. Recommendations for the indication of rheopheresis for AMD should be further defined and evaluated within the framework base of a multicentric cooperative study.

Rheopheresis: rheologic, functional, and structural aspects.

Rheopheresis is a specific application of membrane differential filtration, synonymous with double filtration plasmapheresis for extracorporeal hemorheotherapy, eliminating an exactly defined spectrum of high molecular weight proteins from human plasma (e.g.: fibrinogen, alpha-2-macroglobulin, low-density lipoprotein cholesterol, IgM). This results in the improvement of blood flow and microcirculation initiated by lowering blood and plasma viscosity, and erythrocyte aggregation. In this context, microcirculation stands not only for the patency of small blood vessels, but for the complete interactive network between plasma, blood cells, the vessel wall, and cellular and extracellular compartments of the surrounding tissue. Insufficient tissue oxygenation leads to tissue damage, e.g., a microcirculatory disorder develops, creating acute as well as chronic symptoms. Therefore, impaired microcirculation has a rheologic, functional, and structural dimension with respect to involved organs or tissues. Rheopheresis represents a specific therapeutic approach with an acute rheologic as well as chronic functional and structural effects, which was confirmed in pilot and controlled clinical studies for several organ systems. Data from 2 controlled clinical trials are available for the safe and effective treatment in patients with age-related macular degeneration.

Histone H1 suppresses tumor growth of leukemia cells in vitro, ex vivo and in an animal model suggesting extracellular functions of histones.

Purified histone H1 exerts growth inhibition of leukemia cells independent of lineage, stage, and maturation. At 200 micrograms/ml, H1 proved cytotoxic in 19 of 21 of the tested leukemia-derived cell lines and for 11 of 16 of the fresh tumor samples from leukemia patients. In all cases, normal peripheral blood mononuclear cells and bone marrow cells remained unaffected. Multicellular spheroids from the Burkitt's lymphoma cell line IM-9 were growth arrested at 500 micrograms H1/ml. The clonogenic growth of the Burkitt's lymphoma cell line Daudi was arrested at 160 micrograms H1/ml. Synthetic H1-peptides as well as peptides and proteins with biochemical properties similar to H1 had no inhibitory growth effect at equimolar concentrations. Furthermore, 250 micrograms H1 injected into a Burkitt's lymphoma (Daudi), xenotransplanted into nude mice, arrested tumor growth. As shown by electron microscopy and flow cytometry, incubation of leukemia cells with H1 resulted in severe plasma membrane damage and ultimately cytolysis. This report characterizes a 33-kd protein that binds H1 and is responsible for the cell death via destruction of the cell membrane integrity. New extranuclear functions of histones are presented.

Psychological countermeasures for extended manned spaceflights.

NASA: The authors examine psychological issues and countermeasures in extended space flight. Individual-oriented pre-flight countermeasures include basic psychological selection and training of astronaut candidates. Crew-oriented pre-flight countermeasures include crew composition based on psychological compatibility and psychological mission preparation. Psychological inflight support measures include those that address the emotional state and well-being of astronauts, performance efficiency, and prevention of task overload. Suggestions for an integrated approach to psychological countermeasures for extended flights are presented. Case reports examine psychological selection and training of German astronauts in preparation for the STS-55 mission.^ieng

Implementing human factors training for space crews.

NASA: Psychological aspects of long-term space flight are explored. European and U.S. space programs are contrasted. Human factors training programs address basic human factors training and crew-oriented psychological mission preparation. During the second phase, carefully selected crews focus on support of a team-building process and improvement of crew coordination skills, preventive reduction of inflight crew-load by anticipatory problem-solving, and development of supporting crew skills and preparation of inflight support activities. Elements of the training program were used in preparation of German members of a 1993 European Space Agency confinement study.^ieng

Psychological evaluation of European astronaut applications: results of the 1991 selection campaign.

In the summer of 1991, the European Space Agency (ESA) performed its second selection campaign since 1977 in order to find 10 astronaut candidates (laboratory specialists and space plane specialists). An integral part of this selection process was the psychological evaluation, according to the principles laid down in the study report "Definition of Psychological Testing of Astronaut Candidates." After national preselection, 59 applicants underwent the psychological evaluation, which consisted of the assessment of operational aptitudes (basic cognitive and psychomotor functions) and personality traits (motivation, social capability, stress resistance). The test program included a diverse number of tests, questionnaires, behavioral ratings, biographical data, and semi-structured interviews. About 50 scores were available for each subject. A comparison of the test scores with the original normative data, culture-fairness of the psychological selection, and discriminant functions analyzing the assessment decisions will be presented and discussed.

Determination of GABA and vigabatrin in human plasma by a rapid and simple HPLC method: correlation between clinical response to vigabatrin and increase in plasma GABA.

The novel antiepileptic drug vigabatrin (Sabril) acts by inhibiting degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), increasing the GABA concentrations in the brain. Because the GABA degrading enzyme GABA aminotransferase (GABA-T) is also present in peripheral tissues, including blood platelets, measurement of plasma GABA levels might be a useful indication of the pharmacological response to vigabatrin during therapeutic monitoring. However, because of the very low concentrations of GABA in plasma, the few methods available for plasma GABA analysis are time-consuming, difficult to perform and/or not selective enough because of potential interference with other plasma constituents. In the present study, a rapid, selective and sensitive amino acid analysis HPLC method has been developed for plasma GABA determination with fluorescence detection, using o-phthaldialdehyde as a precolumn derivatizing agent. By employing a 3 microns particle size reversed-phase column and a multi-step gradient system of two solvents, the very low endogenous concentration of GABA in human plasma could be reproducibly quantitated without interference of other endogenous compounds. Incubation of human plasma samples with GABA degrading enzyme(s) resulted in an almost total loss of the GABA peak, thus demonstrating the specificity of the method for GABA analysis. In addition to GABA and other endogenous amino acids, the HPLC method could be used to quantitate plasma levels of vigabatrin. Thus, this improved HPLC amino acid assay might be used to examine whether concomitant monitoring of plasma GABA and vigabatrin is useful for clinical purposes. This was examined in 20 epileptic patients undergoing chronic treatment with vigabatrin. The average plasma GABA level of these 20 patients did not differ significantly from non-epileptic controls. However, when epileptic patients were subdivided according to their clinical response to vigabatrin, vigabatrin responders had significantly higher GABA levels than nonresponders or controls. In contrast to the difference in plasma GABA, vigabatrin responders and nonresponders did not differ in dose or plasma level of vigabatrin. These data may indicate that determination of plasma GABA is a valuable non-invasive method for therapeutic monitoring in patients on medication with vigabatrin.

Results of the ESA study on psychological selection of astronaut applicants for Columbus Missions I: aptitude testing.

European participation in the Space Station Freedom brought about new challenges for the psychological selection of astronaut candidates, particularly in respect to specific demands of long duration space flights. For this reason existing selection criteria and methods were reassessed. On these grounds a study was undertaken applying a unique composition of aptitude tests to a group of 97 ESA scientists and engineers who are highly comparable to the expected astronaut applicants with respect to age and education. The tests assessed operational aptitudes such as logical reasoning, memory function, perception, spatial orientation, attention, psychomotor function, and multiple task capacity. The study goals were: 1) Verification of psychometric qualities and applicability of tests in a normative group; 2) Search for culture-fair tests by which multi-national groups can be examined; 3) Identification of test methods which consider general and special operational demands of long duration space flights. Based on the empirical findings a test battery was arranged for use in the selection of ESA astronaut applicants. Results showed that 16 out of the 18 employed tests have good psychometric qualities and differentiate reliably in the special group of testees. The meta structure of the test battery as described by a factorial analysis is presented. Applicability of tests was generally high. Tests were culture-fair, however, a relation between English language skills and test results was identified. Since most item material was language-free, this was explained with the importance of English language skills for the understanding of test instructions. Solutions to this effect are suggested.

Results of the ESA study on psychological selection of astronaut candidates for Columbus Missions II: personality assessment.

A unique composition of personality assessment methods was applied to a group of 97 ESA scientists and engineers. This group is highly comparable to real astronaut candidates with respect to age and education. The list of used tests includes personality questionnaires, problem solving in groups as well as a projective technique. The study goals were: 1. Verification of psychometric qualities and applicability of tests to the target group; 2. Search for culture-fair tests by which multi-national European groups can be examined; 3. Identification of test methods by which the adaptability of the candidates to the psycho-social stress of long-duration space flights can be assessed. Based on the empirical findings, a test battery was defined which can be used in the selection of ESA space personnel.

Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs.

The anticonvulsant potency of the trans isomer of 2-en-valproate (trans-2-en-VPA) was determined in standardized models for different seizure types in rodents and dogs. In mice and rats, adverse effects were quantified by the rotarod and chimney tests. Clinically established antiepileptic drugs (valproate, ethosuximide, phenobarbital, carbamazepine, phenytoin, diazepam) were used for comparison. Based on time course studies, drug potencies were determined and compared at the individual time of peak anticonvulsant effect. Potency comparisons were based on administered dosages and, in the case of trans-2-en-VPA and valproate, also on plasma levels determined after administration of anticonvulsant doses. The data show that trans-2-en-VPA exerts anticonvulsant effects against different seizure types, i.e., myoclonic, clonic, and tonic seizures in rodents and (myo)clonic seizures in dogs. In most seizure models, trans-2-en-VPA was more potent than valproate, when both compounds were compared at their individual times of peak effect. Time course and pharmacokinetic studies showed that duration of action and pharmacokinetic characteristics of trans-2-en-VPA and valproate are similar. In the rotarod and chimney tests in mice and rats, trans-2-en-VPA was more potent than valproate. However, because of the higher anticonvulsant potency of trans-2-en-VPA, protective indices calculated from rodent models were similar to those of valproate. Similarly, in dogs trans-2-en-VPA exerted anticonvulsant effects at doses below those which induced sedation and ataxia. In view of the previously reported advantages of trans-2-en-VPA compared to valproate with respect to teratogenic and hepatotoxic effects, the present data substantiate that trans-2-en-VPA might be a valuable alternative to valproate in antiepileptic therapy.

Ralitoline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice.

Ralitoline (RLT) is a new thiazolidinone derivative with potent anticonvulsant activity in different seizure models. During Phase I studies, RLT was well tolerated in human volunteers and showed linear pharmacokinetics in the dose range tested (up to 150 mg). Since RLT will soon be entering clinical Phase II studies, we were interested in obtaining predictive data for effective plasma concentrations in patients. For this purpose, the anticonvulsant potency of RLT was determined in four seizure models in mice, and plasma levels were measured at time of peak drug effect. The four models were the threshold for maximal (tonic extension) electroshock seizures (MES), the threshold for clonic seizures determined by i.v. infusion of pentylenetetrazol (PTZ), the traditional MES test with supramaximal (50 mA) stimulation, and generalized clonic seizures induced by s.c. administration of PTZ. Furthermore, median minimal "neurotoxic" doses (TD50s) were determined by the rotorod and chimney test for calculation of protective indices. All data obtained for RLT were compared with data obtained with standard antiepileptic drugs: phenobarbital, phenytoin, valproate, and diazepam. The onset of anticonvulsant action after i.p. injection of RLT was very rapid, and the peak drug effect was already obtained after 2 min. In the MES models, RLT was the most potent compound. "Active" plasma levels ranged from approximately 300 ng/ml in the MES threshold test to approximately 1,300 ng/ml in the MES test. RLT was also capable of increasing the PTZ threshold, whereas, possibly because of its short duration of action in mice, it was not very active in the s.c. PTZ seizure test.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models.

Although seizure models using systemic administration of the chemoconvulsant pentylenetetrazol (PTZ) for induction of generalized clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of diverse technical, biological and pharmacological factors in interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate, and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following PTZ models: (1) the threshold for different types of PTZ seizures, i.e., initial myoclonic twitch, generalized clonus with loss of righting reflexes, and tonic backward extension of forelimbs (forelimb tonus), in mice; (2) the traditional PTZ seizure test with s.c. injection of the CD97 for generalized clonic seizures in mice; and (3) the s.c. PTZ seizure test in rats. In rats, in addition to evaluating drug effects on generalized clonic seizures, a ranking system was used to determine drug effects on other seizure types. When drugs were dissolved in vehicles which themselves did not exert effects on seizure susceptibility, the most important factors which influenced drug potencies were: (1) bishaped dose-response curves, i.e., a decline in anticonvulsant dose-response at high doses of some drugs, leading to misinterpretations of drug efficacy if only a single high drug dosage is tested; (2) effects of route of PTZ administration (i.v. infusion vs. s.c. injection) on estimation of anticonvulsant potency; (3) species differences in drug metabolism; (4) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on 'active' drug concentrations in plasma; (5) qualitative and quantitative species differences in drug actions; (6) endpoints used for PTZ tests; (7) misleading predictions from PTZ seizure models. Analysis of anticonvulsant drug actions indicated that myoclonic or clonic seizures induced by i.v. or s.c. PTZ might be suitable for predicting efficacy against myoclonic petit mal seizures in humans, but certainly not to predict efficacy against absence seizures. Tonic seizures induced by PTZ were blocked by drugs, such as ethosuximide, which exert no effect on tonic seizures in humans. In order to reduce the variability among estimates of anticonvulsant activity in PTZ seizure models, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models.

Although seizure models using electrical stimulation for the induction of generalized tonic-clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of various technical, biological and pharmacological factors in the interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following electroshock seizure models: (1) the maximal (tonic extensor) electroshock seizure threshold (MEST) in mice; (2) the traditional maximal electroshock seizure (MES) test with supra-threshold stimulation in mice; and (3) the MES test with suprathreshold stimulation in rats. When drugs were dissolved in vehicles which did not themselves exert effects on seizure susceptibility, the most important factors which influenced drug potencies were (1) marked differences between drugs and species in terms of peak drug effect, duration of action and the formation of active metabolites; (2) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on active drug concentrations; (3) the equipment used for seizure induction; (4) marked effects of current strength on results obtained in electroshock seizure models; (5) site of application of the electrical stimulus (transcorneal vs. transauricular). In order to reduce the variability among estimates of anticonvulsant activity, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.

Regional alterations in brain amino acids after administration of the N-methyl-D-aspartate receptor antagonists MK-801 and CGP 39551 in rats.

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the novel competitive NMDA receptor antagonist CGP 39551 on levels of 11 amino acids, including several excitatory and inhibitory neurotransmitters, were studied in 12 brain regions of rats. Both drugs were administered at doses which produced comparable behavioural effects (ataxia, hyperactivity). Amino acids were determined in brain tissue by high-performance liquid chromatography after o-phthaldialdehyde precolumn derivatization. MK-801 (0.1 mg/kg, i.p.) moderately increased the concentration of glutamate and GABA in several brain regions. Other amino acids (glutamine, taurine, asparagine, alanine, serine) were only altered in single brain regions, or were not altered at all (aspartate, glycine, threonine, arginine). In contrast to MK-801, CGP 39551 (10 mg/kg, i.p.) increased glutamate levels only in the cerebellum, and produced no significant alterations in levels of GABA. The data demonstrate differences in alterations of amino acid levels in response to competitive and non-competitive NMDA receptor antagonists and support the assumption that competitive NMDA antagonists may be more selective than non-competitive antagonists.