Competitive NMDA-Receptor Antagonists, LY 235959 and LY 233053, Enhance the Protective Efficacy of Various Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-quinoline-3-carboxylic acid; 50.5 mgikg] or LY 233053 [cis-(±)-4–[(2H-tetrazol-5–yl) methyl] piperidine-2-carboxylic acid; 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (=0.5 and 5 mg/kg, respectively) did not influence the electroconvul sive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydan-toin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.     

Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice

Rationale  

Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs.     

Can general cardiovascular risk evaluation facilitate the assessment of fitness for work and contribute to the reduction of cardiovascular incidents among seamen and fishermen? Article for discussion

Apart from accidents and work related injuries caused by external factors, being the primary cause of death at sea and repatriation of seamen and fishermen from ship to hospital on shore, acute cardiovascular incidents are the main internal causes of their death, both at sea and on land, as well as of long lasting sick leave and disability. In the regulations on health requirements for persons working on sea-going ships and in inland navigation (orders of the Ministry of Health 1993, 1996, 2003, guidelines (39), EU directives and other national regulations) and in the register of diseases and conditions disqualifying from such an employment (EU directive, annex to the order of the Ministry of Health 1993, European Commission (32,33), ILO/WHO guidelines, cardiovascular diseases are only generally mentioned. The minimal scope of examinations is recommended for seafarers in age up to 50 years, and for older seafarers, but without the assessment of their occupational risk. This gives rise to ambiguities in interpretation at the time of issuing their health certificates, and also in judicature when analyzing cause-and-effect relationship between the occurrence of an acute cardiovascular incident during the ship's voyage and conditions of the work at sea. Principles, possibilities and benefits are discussed in this paper, which may be expected from the general assessment of cardiovascular diseases risk at the time of the health assessment for the work at sea. The risk forecasting, health certification and the question of choosing primary preventive methods are included in this presentation.     

Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae

Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.     

Diabetes and work at sea: has everything been already settled? Article for discussion

Along with increased worldwide incidence of diabetes, the frequency of its occurrence among persons employed on seagoing vessels has also grown (12). According to the current regulations, persons treated with insulin are not admitted to work at sea, and those treated with oral drugs have a markedly limited access to such a work. This may lead to concealing the fact of being a diabetic, thus enhancing the existing hazards. Current improved methods of glycemia self-control and treatment of diabetes have radically improved vital abilities of diabetics. Having this in mind, a question arises whether the binding regulations on the fitness of diabetics for work at sea should be verified.     

The visual acuity impairment as the only sign of cerebral aneurysms--case report

Cerebral aneurysms are the most common reason of subarachnoid haemorrhage at the age of 50-60. Though the results of such haemorrhage are severe (high morbidity and mortality), it is quite often, the first noticeable sign of the problem. Previous symptoms i. e. headache, ophthalmic disturbances, temporary neurological symptoms are often passed over. The authors present the case of a young woman with cerebral aneurysms, in which the visual acuity impairment was the only symptom of the disease.     

Why human pemphigoid autoantibodies do not trigger disease by the passive transfer into mice?

The recapitulation of disease features in animals by the transfer of patient autoantibodies has been used to demonstrate the autoimmune nature of several diseases. Failure of disease induction by the passive transfer of autoantibodies has been assigned to a limited cross-reactivity of the autoantibodies with the murine tissue. However, the possibility that the passively transferred "inflammatory" patient autoantibodies may not be able to unfold their pathogenic potential due to restricted Fc-dependent effector functions has not yet been systematically explored. In this study we analyze the interaction of patients' autoantibodies with murine complement and granulocytes. Bullous pemphigoid is a blistering disease associated with autoantibodies, which are thought to induce subepidermal blistering by activating complement and granulocytes. The passive transfer of patients autoantibodies failed to induce skin blistering in wild type mice. The cross-reactivity of pemphigoid autoantibodies with murine antigens was analyzed in silico, ex vivo and by the passive transfer of IgG in vivo. Complement-fixing ability of patients' autoantibodies was evaluated by complement-binding test. Granulocyte activation was assessed by reactive oxygen species production assay and the cryosection model. We have found that although pemphigoid autoantibodies bound to murine skin in vitro and in vivo, they showed a lower capacity to fix murine complement and a reduced ability to activate murine granulocytes when compared with human complement and cells, respectively. These results indicate that for disease models using the passive transfer of patient autoantibodies, their interaction with the innate factors of the host should be optimized to match the human situation.     

The effects of orexins on monoaminerg-induced changes in vasopressin level in rat neurohypophyseal cell cultures

The effects of orexin–monoaminergic compound interactions on vasopressin release were studied in 14-day neurohypophyseal cell cultures from adult rats, prepared by an enzymatic dissociation technique. The vasopressin contents of the supernatants were determined by radioimmunoassay. Following administration of either orexin-A or orexin-B in increasing doses, significant changes were not observed in the vasopressin levels of the supernatant media. The vasopressin level substantially increased after epinephrine, norepinephrine, serotonin, histamine, dopamine or K⁺ treatment. Preincubation with either orexin-A or orexin-B reduced the epinephrine-, histamine- or serotonin-induced increases in vasopressin level, but the vasopressin concentrations of the supernatant media remained above the control level. There was no significant difference in decreasing effect between orexin-A and orexin-B. Neither orexin-A nor orexin-B induced changes in vasopressin release following monoaminergic compound treatment. The results indicate that the changes in vasopressin secretion induced by the monoaminergic system can be directly influenced by orexin system. It may be presumed that the orexins can play a physiological role in the regulation of the water metabolism by reducing the effect of increased vasopressin release caused by monoaminergic compounds. The interactions between the monoaminergic and orexin systems regarding vasopressin secretion occur at both the hypothalamic and the neurohypophyseal level.