Efficacy and Safety of Low-Dose Versus Standard-Dose Alteplase Regimens in Patients with Acute Ischaemic Stroke.

BACKGROUND: The use of intravenous recombinant tissue plasminogen activator, alteplase, at a dose of 0.9 mg/kg is an effective treatment for patients with acute ischaemic stroke; this dose is also associated with high intracerebral haemorrhage rates. The aim of this study was to evaluate whether the low-dose alteplase treatment is as effective and safe as the standard-dose regimen. SUBJECTS AND METHODS: This was a retrospective, single-centre study, and data were collected from the Hospital Stroke Registry. Based on the severity of stroke and the risk of intracerebral haemorrhage, patients were divided into two groups according to the alteplase doses given; the low-dose (0.6 mg/kg) group (n=45) and the standard-dose (0.9 mg/kg) group (n=165). Ninety-day outcomes measured as modified Rankin score and National Institute for Health Stroke Scale (NIHSS) score, as well as symptomatic intracerebral haemorrhage and mortality rates were analysed. RESULTS: The standard-dose group had a slightly more favourable outcome (Rankin score 0-2) at 90 days after alteplase treatment than the low-dose group (64.24% vs. 53.33%), but the difference was not significant. The total intracerebral haemorrhage rate and mortality rate at 90 days were higher in the standard-dose group than in the low-dose group (21.2% vs. 13.3% and 6.1% vs. 0.0%, respectively), but these differences were not statistically significant. CONCLUSION: The low-dose alteplase treatment applied to the patients with high intracerebral haemorrhage risk had comparable efficacy and safety profile to the standard-dose regimen.

The Efficacy of Amifostine against Multiple-Dose Doxorubicin-Induced Toxicity in Rats.

Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

Protective effects of glucose-6-phosphate dehydrogenase on neurotoxicity of aluminium applied into the CA1 sector of rat hippocampus.

BACKGROUND & OBJECTIVES: Aluminum (Al) toxicity is closely linked to the pathogenesis of Alzheimer's disease (AD). This experimental study was aimed to investigate the active avoidance behaviour of rats after intrahippocampal injection of Al, and biochemical and immunohistochemical changes in three bilateral brain structures namely, forebrain cortex (FBCx), hippocampus and basal forebrain (BF). METHODS: Seven days after intra-hippocampal (CA1 sector) injection of AlCl3 into adult male Wistar rats they were subjected to two-way active avoidance (AA) tests over five consecutive days. Control rats were treated with 0.9% w/v saline. The animals were decapitated on the day 12 post-injection. The activities of acetylcholinesterase (AChE) and glucose-6-phosphate dehydrogenase (G6PDH) were measured in the FBCx, hippocampus and BF. Immunohistochemical staining was performed for transferrin receptors, amyloid ß and tau protein. RESULTS: The activities of both AChE and G6PDH were found to be decreased bilaterally in the FBCx, hippocampus and basal forebrain compared to those of control rats. The number of correct AA responses was reduced by AlCl3 treatment. G6PDH administered prior to AlCl 3 resulted in a reversal of the effects of AlCl3 on both biochemical and behavioural parameters. Strong immunohistochemical staining of transferrin receptors was found bilaterally in the FBCx and the hippocampus in all three study groups. In addition, very strong amyloid ß staining was detected bilaterally in all structures in AlCl3-treated rats but was moderate in G6PDH/AlCl3-treated rats. Strong tau staining was noted bilaterally in AlCl3-treated rats. In contrast, tau staining was only moderate in G6PDH/AlCl3-treated rats. INTERPRETATION & CONCLUSIONS: Our findings indicated that the G6PDH alleviated the signs of behavioural and biochemical effects of AlCl3-treatment suggesting its involvement in the pathogenesis of Al neurotoxicity and its potential therapeutic benefit. The present model could serve as a useful tool in AD investigations.

Influence of the green tea leaf extract on neurotoxicity of aluminium chloride in rats.

Aluminium may have an important role in the aetiology/pathogenesis/precipitation of Alzheimer's disease. Because green tea (Camellia sinensis L.) reportedly has health-promoting effects in the central nervous system, we evaluated the effects of green tea leaf extract (GTLE) on aluminium chloride (AlCl3 ) neurotoxicity in rats. All solutions were injected into the cornu ammonis region 1 hippocampal region. We measured the performance of active avoidance (AA) tasks, various enzyme activities and total glutathione content (TGC) in the forebrain cortex (FbC), striatum, basal forebrain (BFb), hippocampus, brain stem and cerebellum. AlCl3 markedly reduced AA performance and activities of cytochrome c oxidase (COX) and acetylcholinesterase (AChE) in all regions. It decreased TGC in the FbC, striatum, BFb, hippocampus, brain stem and cerebellum, and increased superoxide dismutase activity in the FbC, cerebellum and BFb. GTLE pretreatment completely reversed the damaging effects of AlCl3 on AA and superoxide dismutase activity, markedly corrected COX and AChE activities, and moderately improved TGC. GTLE alone increased COX and AChE activities in almost all regions. GTLE reduces AlCl3 neurotoxicity probably via antioxidative effects and improves mitochondrial and cholinergic synaptic functions through the actions of (-)-epigallocatechin gallate and (-)-epicatechin, compounds most abundantly found in GTLE. Our results suggest that green tea might be beneficial in Alzheimer's disease.

The influence of comedication on tacrolimus blood concentration in patients subjected to kidney transplantation: a retrospective study.

Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers, diuretics and proton pump inhibitors (PPIs) significantly affected TTC (p < 0.001). PPIs significantly increased the number of examinations in which the TTC were in the recommended therapeutic range (from 5 to 15 ng/ml), as well as over the therapeutic range (p < 0.0001). When calcium channel blockers were added to PPIs, even more pronounced effect was obtained in comparison to triple-drug therapy only (p < 0.0001). In case a diuretic was given with a PPI, a significantly increased number of examinations with subtherapeutic TTC was observed when compared with PPI only (p = 0.0203). The combination of calcium channel blockers, diuretics and PPIs resulted in the number of examinations with TTC in the recommended therapeutic range not being different from the number of examinations with TTC in the triple-drug therapy only (p = 0.3829). ß-adrenergic antagonists can be administered without fear of affecting the tacrolimus optimal therapeutic concentrations. This was confirmed with all combinations of the examined drugs used in patients subjected to kidney transplantation concomitantly with ß blockers.

Effects of memantine and its metabolite Mrz 2/373 on soman-induced inhibition of acetylcholinesterase in vitro.

Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.

Sex and Time-of-Day Impact on Anxiety and Passive Avoidance Memory Strategies in Mice.

In humans, anxiety and cognitive processes are age, gender, and time of day dependent. The purpose of the present study was to assess whether the time of day and sex have an influence on anxiety and emotional memory in adult mice. Light-dark and passive avoidance (PA) tests were performed at the beginning and at the end of the light cycle, defined as Zeitgeber time (ZT) ZT0-2.5 and ZT9.5-12, respectively. A baseline difference in anxiety was not found, but on the 24 h retention trial of the PA test, females presented longer latencies to enter into the dark compartment at the ZT0-2.5 time point of the day. The data from the second test day (PA reversal trial) indicated that some animals associated the dark compartment with an aversive stimulus (shock), while others associated the aversive stimulus with crossing from one compartment to another. At the ZT9.5-12, female mice mainly related the aversive stimulus to transferring from one compartment to another, while male mice associated darkness with the aversive stimulus. There was a negative correlation between the frequency of light-dark transitions in the light-dark test and the PA latency on the 24 h retention trial in males tested at ZT0-2.5. The PA latency on the reversal and 24 h retention trials negatively correlated with a risk assessment behavior in male mice tested on ZT0-2.5 and ZT9.5-12, respectively. In conclusion, our data reveal that the impact of motor activity and risk assessment behavior on PA memory formation and applied behavioral strategies are time of day and sex dependent.

Systemic and intraperitoneal proinflammatory cytokine profiles in patients on continuous ambulatory peritoneal dialysis.

Our cross-sectional study included 44 patients (27 men, 17 women; mean age: 57.12 +/- 16.66 years; mean dialysis treatment period: 3.59 +/- 2.67 years) on continuous ambulatory peritoneal dialysis (CAPD). Of the 44 patients, 21 were using standard solutions (Stay*Safe, ANDY-disc: Fresenius Medical Care, Bad Homburg, Germany), and 23 were using biocompatible solutions (Gambrosol Trio: Gambro Lundia AB, Lund, Sweden; Stay*Safe Balance: Fresenius Medical Care). In all CAPD patients dialyzed longer than 6 months, we analyzed levels of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interleukin 6 (IL-6) in serum and dialysis effluent when patients were free of acute infection-related (CAPD peritonitis, exit-site infection, other acute infections) complications. In a control group of 20 patients with chronic renal failure [CRF (stages IV and V)], we also determined serum levels of the same cytokines. Levels of the inflammatory cytokines were measured using specific commercial ELISA kits (BioSource, Camarillo, CA, U.S.A.). Statistical analysis of the results was performed using commercial statistics software for the PC (Statistica for Windows, rev. 4.5: StatSoft, Tulsa, OK, U.S.A.). Serum levels of LL-1beta and IL-6 were not statistically significantly different between the patients on CAPD, regardless of the type of dialysis the used, and between the patients and the control group with CRF. Serum levels of TNFalpha, unlike those for IL-1beta and IL-6, were statistically significantly higher in patients on CAPD than in the control group with CRF (13.20 +/- 3.23 pg/mL vs. 5.59 +/- 4.54 pg/mL, p < 0.001, Mann-Whitney test). Serum and effluent IL-1beta levels in patients on CAPD for less than 1 year and more than 1 year did not significantly differ, but effluent IL-6 levels were significantly higher than serum IL-6 levels in both groups of patients, and effluent IL-6 levels were significantly higher in CAPD patients dialyzed for more than 1 year than in patients dialyzed for less than 1 year. Serum and intraperitoneal (IP) levels of the examined cytokines did not significantly differ in patients on standard and biocompatible solutions, but a trend toward lower IP levels of IL-6 was seen in patients on biocompatible solutions. Residual renal function and number of episodes of CAPD peritonitis had no important effect on serum and IP levels of the examined cytokines. Elevated serum levels of TNFalpha and significant local IL-6 production in our CAPD patients indirectly confirmed the importance of peritoneal dialysis (PD) in amplifying the chronic inflammation that substantially depends on duration of dialysis treatment.

Prophylactic potential of memantine against soman poisoning in rats.

BACKGROUND: Carbamates physostigmine and pyridostigmine have been used as a pretreatment against poisoning with nerve agents in order to reversibly inhibit and thus protect from irreversible inhibition a portion of acetylcholinesterase (AChE) in brain and respiratory muscles that is crucial for survival. Memantine, an adamantine derivative, has emerged as a promising alternative to carbamates, since it prevented the fasciculations and skeletal muscle necrosis induced by carbamates and organophosphates, including nerve agents. AIM: This experimental study was undertaken in order to investigate and compare the protective and behavioural effects of memantine and standard carbamates physostigmine and pyridostigmine in rats poisoned with soman and treated with atropine, oxime HI-6 and diazepam. Another goal was to elucidate the mechanisms of the antidotal effect of memantine and its potential synergism with standard antidotes against nerve agents. MATERIALS AND METHODS: Male Wistar rats were used throughout the experiments. In dose-finding experiments memantine was administered at dose interval 0-72 mg/kg sc 60 min before sc injection of soman. In time-finding experiments memantine was injected 18 mg/kg sc 0-1440 min before soman. Standard treatment antidotes - atropine 10 mg/kg, HI-6 50 mg/kg and diazepam 2.5 mg/kg - were administered im within 15 s post-exposure. Soman 0.75 LD50 was used to study its inhibitions of neuromuscular transmission on the phrenic nerve-diaphragm preparation in situ and of tissue AChE activity. Behavioural effects of the prophylactic antidotes were investigated by means of the rotarod test. Based on these data therapeutic index and therapeutic width was calculated for all three prophylactic agents. RESULTS: Memantine pretreatment (18 mg/kg sc) produced in rats poisoned with soman significantly better protective ratios (PRs) than the two carbamates - 1.25 when administered alone and 2.3 when combined with atropine pretreatment and 6.33 and 7.23 with atropine/HI-6 and atropine/HI-6/diazepam post-exposure therapy, respectively. The highest PR of 10.11 obtained in Atr/HI-6-treated rats was achieved after pretreatment with memantine 36 mg/kg. This additional protection lasted for 8 h. All three prophylactic regimens antagonised the soman-induced neuromuscular blockade, but the effect of memantine was fastest. Pretreatment with memantine assured higher AChE activity in brain and diaphragm than in unpretreated rats (46% vs 28% and 68% vs. 38%, respectively). All three prophylactic regimens affected the rotarod performance in rats, but the effect of memantine was relatively strongest. Memantine and pyridostigmine had lowest and highest therapeutic index and therapeutic width, respectively. CONCLUSIONS: Although memantine assures better and longer-lasting protection against soman poisoning in rats than the two carbamates, its small therapeutic index and narrow therapeutic width seriously limit its potential as a pretreatment agent. Despite its behavioural effects, memantine seems to be beneficial antidote when administered after soman, along with atropine/HI-6/diazepam therapy. Mechanism of the antidotal effect of memantine against soman poisoning appears to be a combination of AChE-protecting and NMDA receptor-blocking action.

Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA(A) receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

Beneficial effects of ceftriaxone against pentylenetetrazole-evoked convulsions.

Although considered to be generally safe, a number of beta-lactam antibiotics have been associated with epileptic seizures in humans. Furthermore, some beta-lactam antibiotics, including ceftriaxone, are used to evoke convulsions under experimental conditions. Recently it was demonstrated that ceftriaxone increased expression of the glutamate transporter (GLT1) and its biochemical and functional activity in the brain of rodents. GLT1 regulates extracellular concentrations of glutamate, an excitatory amino acid involved in the pathogenesis of seizures and epilepsy. Because of its rapid transfer of glutamate into neurons and adjacent glial cells, GLT1 diminishes glutamate toxicity. We investigated whether ceftriaxone (200 mg/kg body wt) administered intraperitoneally (ip) for 6 days could modify the convulsant effects of pentylenetetrazole (PTZ, 100 mg/kg ip) in inbred male BALBcAnNCR and C57 black (BL)/6 mice aged 4 and 12 weeks. Ceftriaxone pretreatment provided significant protective effects against PTZ-evoked generalized clonic convulsions (GCCs), generalized clonic-tonic convulsions (GCTCs), and convulsion-induced mortality during a period of 30 mins after PTZ administration. The incidence of GCCs, GCTCs, and death was statistically significantly lower for BALBcAnNCR mice of both ages, particularly younger mice. The latency time for each of the three parameters was significantly greater, with the exception of GCCs in adult mice. Protective effects of ceftriaxone were also noticed in adult C57BL/6 mice but not in prepubertal C57BL/6 mice. This is the first demonstration of anticonvulsant effects of ceftriaxone or any other beta-lactam antibiotic, which are not uniform across the mouse population. Our results provide new insight into the effects of ceftriaxone, which need further investigation.

Efficacy of antidotes and their combinations in the treatment of acute carbamate poisoning in rats.

BACKGROUND: Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer's disease and prophylaxis against nerve agent intoxications. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes. AIM: The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d-tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine. MATERIALS AND METHODS: Experiments were performed in Wistar rats. Carbamates were injected subcutaneously (sc) and antidotes intramuscularly (im). Median lethal dose (LD50) in animals treated with antidotes were compared to the ones in saline-treated rats and protective ratios (PRs) were calculated. Atropine (5, 10 and 20 mg/kg), hexamethonium (5, 10 and 20 mg/kg), d-tubocurarine (0.005, 0.010 and 0.020 mg/kg) and oxime HI-6 (25, 50 and 100 mg/kg) were used as monotherapies and in dual combinations, where atropine was the obligatory antidote. Biochemical experiments consisted in measuring of the cholinesterase activities in brain, whole blood and diaphragm in rats 5, 15, 30, 60, 120 and 240 min after poisoning with 0.8 LD50 of physostigmine or pyridostigmine. RESULTS: All the tested antidotes assured some degree of protection against the two carbamates. Atropine and hexamethonium produced better protection in physostigmine-poisoned rats, while d-tubocurarine and HI-6 were more efficacious in pyridostigmine-intoxicated animals. Oxime HI-6 50 mg/kg reactivated acetylcholinesterase (AChE) in brain inhibited by physostigmine and in diaphragm inhibited by pyridostigmine. CONCLUSIONS: Mechanism of physostigmine-induced lethal effect is predominantly central and it involves inhibition of brain AChE, while pyridostigmine produces the same effect exclusively outside the central nervous system, by inhibiting AChE in the respiratory muscles. As a consequence, increasing doses of atropine and their combination with hexamethonium assure excellent protection against physostigmine toxicity, while the best protection against pyridostigmine is provided by a strictly peripherally acting antinicotinic d-tubocurarine and bispyridinium oxime HI-6. The oxime acts as antidote against physostigmine and pyridostigmine poisoning by reactivating AChE in the brain and diaphragm, respectively.

Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study.

BACKGROUND: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations. RESEARCH DESIGN AND METHODS: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC0-72h, AUC0-∝, Cmax, Tmax, T1/2 and Kel. RESULTS: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events. CONCLUSIONS: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.

Disability, Work Absenteeism, Sickness Benefits, and Cancer in Selected European OECD Countries-Forecasts to 2020.

BACKGROUND: Disability either due to illness, aging, or both causes remains an essential contributor shaping European labor markets. Ability of modern day welfare states to compensate an impaired work ability and absenteeism arising from incapacity is very diverse. The aims of this study were to establish and explain intercountry differences among selected European OECD countries and to provide forecasts of future work absenteeism and expenditures on wage replacement benefits. METHODS: Two major public registries, European health for all database and Organization for Economic Co-operation and Development database (OECD Health Data), were coupled to form a joint database on 12 core indicators. These were related to disability, work absenteeism, and sickness benefits in European OECD countries. Time horizon 1989-2013 was observed. Forecasting analysis was done on mean values of all data for each single variable for all observed countries in a single year. Trends were predicted on a selected time horizon based on the mean value, in our case, 7 years up to 2020. For this purpose, ARIMA prediction model was applied, and its significance was assessed using Ljung-Box Q test. RESULTS: Our forecasts based on ARIMA modeling of available data indicate that up to 2020, most European countries will experience downfall of absenteeism from work due to illness. The number of citizens receiving social/disability benefits and the number being compensated due to health-related absence from work will decline. As opposed to these trends, cancer morbidity may become the top ranked disability driver as hospital discharge diagnoses. Concerning development is the anticipated bold growth of hospital discharge frequencies due to cancer across the region. This effectively means that part of these savings on social support expenditure shall effectively be spent to combat strong cancer morbidity as the major driver of disability. CONCLUSION: We have clearly growing work load for the national health systems attributable to the clinical oncology acting as the major disability contributor. This effectively means that large share of these savings on public expenditure shall effectively be spent to combat strong cancer morbidity. On another side, we have all signs of falling societal responsibility toward the citizens suffering from diverse kinds of incapacity or impaired working ability and independence. Citizens suffering from any of these causes are likely to experience progressively less social support and publicly funded care and work support compared to the golden welfare era of previous decades.

The lack of bicuculline and picrotoxin influence on midazolam depressant action on brain oxygen consumption.

In the previous study of the rat frontal cortex slices oxygen consumption (QO2), polarographically determined using the biological oxygen monitor, a moderate respiratory depressant action of midazolam ex vivo (1.0 mg/kg) has been observed. Antagonist of the benzodiazepine binding site, flumazenil, blocked the effect of the agonist. However, midazolam-gamma-aminobutyric acid (GABA) interactions pointed to the possibility that a part of midazolam action is independent of the classical GABA potentiation. To test this presumption, GABAA receptor antagonists bicuculline and picrotoxin were administered. Both blockers antagonized the QO2 reducing effect of the combination of per se effective doses of midazolam (1.0 mg/kg) and GABA (5 x 10(-4) mol/l), as well as of GABA (5 x 10(-4) mol/l) itself. However, neither effects of midazolam (1.0 mg/kg) on its own, nor those of midazolam in presence of the physiological, per se ineffective, concentration of GABA (10(-6) mol/l), were susceptible to antagonism. These results show that ex vivo influence of midazolam on cerebral metabolic activity should be partly ascribed to some of its cellular mechanisms probably associated to the GABA modulation, but distinct from the standard GABA-potentiating effects of benzodiazepines.

Benzodiazepine site inverse agonists and locomotor activity in rats: bimodal and biphasic influence.

Benzodiazepine site inverse agonists may increase or decrease locomotor activity in rodents, depending on the experimental settings. We have compared the behavioral responses to environmental novelty of rats treated with the non-selective inverse agonist DMCM (2 mg/kg) and the alpha1-subunit affinity-selective inverse agonist 3-EBC (15 mg/kg). The behavior in spontaneous locomotor assay (during 45 min) and elevated plus maze (EPM) was automatically recorded. In the EPM, general activity-related parameters were similarly decreased, whereas only DMCM inhibited open-arm activity. In the locomotor assay, both compounds depressed locomotion in the first 15 min and activity in the central zone of the chamber. However, the influence of 3-EBC was less pronounced. The alpha1-subunit selective antagonist beta-CCt (15 mg/kg) attenuated locomotor depression, but not the central-zone avoidance elicited by DMCM. When habituated to the chamber, DMCM-treated animals emitted a plateau phase of activity, which disappeared by adding beta-CCt. Hence, inhibition of activity in exposed areas may be mediated by non-alpha1-subunits, whereas both alpha1 and non-alpha1-subunits may participate in suppression of activity in more protective areas of an apparatus. Hyperlocomotion in habituated animals may depend primarily on the alpha1-subunit. Moreover, the bimodal influence of inverse agonists on locomotion can be biphasic, observable in the same experiment.

Effect of sodium bicarbonate in rats acutely poisoned with dichlorvos.

The development of effective antidotes against organophosphates such as dichlorvos has been a persistent challenge over the past decades. Therapy of organophosphate poisoning is based on the administration of atropine and oxime as standard antidotes. The present study was undertaken to evaluate the ability of sodium bicarbonate to improve protective effects of standard antidotes in rats poisoned with dichlorvos. The aim of this experiment was to establish the correlation between protective effects and biochemical parameters relevant for acid-base status. In order to examine the protective effect of both standard antidotes and their combinations, groups of experimental animals were poisoned subcutaneously with increasing doses of dichlorvos. Immediately thereafter, rats were treated with atropine 10 mg/kg intramuscularly, oximes 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally. These antidotes were administered either as single doses or in combinations. In the biochemical part of the experiments, rats were poisoned with dichlorvos 1.3 LD(50) (10.64 mg/kg) subcutaneously and immediately thereafter treated with atropine 10 mg/kg intramuscularly, oximes (trimedoxime or obidoxime) 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally either as single doses or in combinations. Parameters relevant for acid-base status were measured 10 minutes after the administration of antidotes. The results of our study indicate that addition of sodium bicarbonate to standard antidotes significantly improves protective effects of atropine, obidoxime and trimedoxime. Correlation between protection and biochemical outcome is clearly evident when sodium bicarbonate is being added to atropine.

In-hospital mortality analysis in patients with proximal femoral fracture operatively treated by hip arthroplasty procedure.

BACKGROUND/AIM: Hip fracture remains the leading cause of death in trauma among elderly population and is a great burden to national health services. In-patient death analysis is important to evaluate risk factors, make appropriate selection and perform adequate treatment of infections for patients to be operated. The aim of this study was to analyze in-hospital mortality in proximal femoral fracture patients operatively treated with hip arthroplasty procedure. METHODS: We followed 622 consecutive patients, and collected data about age, gender, the presence of infection preoperatively and postoperatively, American Society of Anesthesiologists (ASA) score, diabetes mellitus and the type of surgical procedure. Postoperative infections included pneumonia, urinary tract infections, surgical site infections and sepsis. RESULTS: We found a statistically significant influence of preoperative and postoperative infection presence for in-patient mortality with relative risk for lethal outcome of 4.53 (95% CI: 1.44-14.22) for patients with preoperative infection and 7.5 (95% CI: 1.90-29.48) for patients with postoperative infection. We did not confirm a statistically significant influence of age, gender, ASA score, diabetes mellitus or the type of surgical procedure for increased mortality rate. CONCLUSION: Adequate preoperative selection, risk evaluation and adequate treatment of infections are of the key importance for lowering the risk of death in patients operated due to proximal femoral fracture and treated by hip arthroplasty procedures. Special attention is to be paid for the presence of preoperative and postoperative infections in patients operatively treated due to the risk for increased in-hospital mortality.

Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and beta-CCt.

RATIONALE: The pharmacological approach, using subtype selective ligands, complements genetic studies on the specific contribution of individual receptor subtypes to the various effects of benzodiazepines. OBJECTIVE: The aim of this study was to examine the relative significance of alpha1-containing GABA(A) receptors in the effects of modulators at the benzodiazepine site on anxiety and memory processes. METHODS: We tested the effects of the nonselective antagonist flumazenil, the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), the nonselective agonist midazolam, the preferential alpha1-subunit selective agonist zolpidem, and the nonselective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in a two-way active avoidance task in rats. The influence of flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg) on the effects of the two agonists were also examined. In the schedule 2 x 30 trials, drugs were administered i.p. 20 min before the training session. Avoidance responses in the training session are an anxiety-mediated behavior, whereas performance in the retention session relates to the effects on memory. RESULTS: Flumazenil and beta-CCt did not affect behavior. Midazolam (2.0 mg/kg) facilitated acquisition performance, while DMCM (1.0 and 2.0 mg/kg) induced the opposite effect. Flumazenil antagonized both effects. Beta-CCt potentiated the effect of midazolam, and partly antagonized the effect of DMCM. Midazolam (0.5 and 1.0 mg/kg) and zolpidem (1.0-3.0 mg/kg) impaired, while DMCM (0.1 mg/kg) facilitated the subjects' performance in the retention test. The amnesic effects were attenuated but not fully reversed, while the effect of DMCM was counteracted by both antagonists. CONCLUSION: The results indicate the alpha1-subunit interferes with the anxiolytic effect of a benzodiazepine site agonist and may contribute to the DMCM-induced anxiogenic effect. It is also substantially involved in the bidirectional memory processing in the active avoidance paradigm.

Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt.

Recent research on genetically modified mice has attributed the amnesic effect of benzodiazepines mainly to the alpha1-containing GABA(A) receptor subtypes. The pharmacological approach, using subtype selective ligands, is needed to complement genetic studies. We tested the effects of the non-selective antagonist flumazenil (0-20.0 mg/kg), the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) (0-30.0 mg/kg), the non-selective agonist midazolam (0-2.0 mg/kg), the preferential alpha1-subunit selective agonist zolpidem (0-3.0 mg/kg), and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0-2.0 mg/kg) in the one-trial step-through passive avoidance task in rats. The compounds were administered intraperitoneally, before the acquisition test. Flumazenil and beta-CCt did not affect retention performance. Midazolam and zolpidem induced amnesia in a dose-dependent manner. The complete reversal of amnesia was unattainable. The effects of zolpidem were significantly attenuated by the both, flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg); by contrast, only flumazenil was considerably effective when combined with midazolam. DMCM exerted promnesic effects at 0.2mg/kg, in an inverted U-shape manner. Both antagonists tended to abolish this action. The results indicate that some other alpha-subunit(s), in addition to the alpha1-subunit, contribute to the amnesic actions of non-selective benzodiazepine site agonists in the passive avoidance task. On the other hand, a significant part of the DMCM-induced promnesic effect could involve the alpha1-subunit and/or other putative beta-CCt-sensitive binding site(s).