Two propofol formulations are equivalent in small children aged 1 month to 3 years.

BACKGROUND: Propofol has been widely used in general anesthesia. Although it is also often used in pediatric anesthesia, there has been only limited scientific evidence on the use of propofol in children up to 3 years. METHODS: A prospective, randomized, double-blind, therapeutic equivalence study comparing two propofol 1% emulsions (Propofol 1% Fresenius vs. Diprivan 1%) was performed in 60 patients scheduled for routine surgery or for diagnostic laparoscopic procedures requiring anesthesia. To guarantee comparability of age distribution between the two groups, a stratified randomization with patients younger than 12 months of age in a low age group and with patients aged 12 months to 3 years in a high age group was used. The average propofol induction dose and the average propofol infusion dose were analyzed to prove equivalence. The side-effects profile was analyzed to compare the safety profiles of the two propofol formulations in this study. RESULTS: There were no differences in baseline characteristics between the two treatment groups of high and low age. Medications used for induction and maintenance of anesthesia, and side-effects profiles were comparable, as were the average propofol dose for induction of anesthesia (range of the mean dose 4.0-4.2 mg/kg) and for maintenance of anesthesia (range of the mean dose in the first hour 8.74-9.42 mg x kg(-1) x h(-1)). CONCLUSIONS: The two 1% propofol formulations were equally effective in our patient population of infants and young children between 1 month and 3 years of age. No differences between the two propofol formulations were found with regard to the circulatory reaction, lipid metabolism, dosages, and recovery profile in the studied age groups.

The drug cerebrolysin and its peptide fraction E021 increase the abundance of the blood-brain barrier GLUT1 glucose transporter in brains of young and old rats.

The brain-derived peptidergic drug Cerebrolysin has been found to support the survival of neurons in vitro and in vivo. In the present study, we investigated the effects of Cerebrolysin and its peptide preparation E021 on spatial learning and memory, as well as on the abundance of the blood-brain barrier GLUT1 glucose transporter (GLUT1) in 2-month-old and 24-month-old rats. Young rats were treated with the drugs or saline (2.5 ml/kg/day) daily on postnatal days 1-7, and old rats for 19 consecutive days. For behavioural testing the Morris water maze was used. The abundance of GLUT1 was determined in brain slices by immunocytochemistry. Quantification of the density of the GLUT1 immunostaining was performed using light microscopy and a computerised image analysing system. All drug-treated rats, young and old, exhibit shorter escape latencies in the water maze, on all testing days (p < 0.01), indicating improved cognitive performance. Immunohistochemical data show an age-related decrease of the density of GLUTI (p < 0.05). In young animals, the administration of the drugs led to an increase of the abundance of GLUT1 in all experimental groups (p < 0.01). In old rats, the treatment with Cerebrolysin, but not with E021, resulted in an increase in the immunoreactive GLUT1 (p < 0.01). The elevated abundance of GLUT1 after the administration of both peptidergic substances might be supportive for the cognitive effects of this drug, by causing an improved nutritional supply of glucose to the neurons.

Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 6-week-old rats.

An increase of synaptic density has been found in the hippocampus, the dendate gyrus and in the entorhinal cortex of 6-week-old rats after 7 days of treatment with the peptidergic drug Cerebrolysin, its peptide preparation E021 and the diluted peptide preparation E021dil. Rats received drugs on postnatal days 1-7 (2.5 ml/kg, each day). Controls received saline. The animals were sacrificed on days 42-48 of their life, after they had undergone behavioural testing in a Morris water maze. Slices of brain were stained immunohistochemically with anti-synaptophysin, a specific marker of presynaptic terminals. The synaptophysin-immunoreactivity of presynaptic terminals was quantified using light microscopy and a computerised image analysis system. Our results showed that rats benefit from the treatment with both drugs. A significant increase in the number of synaptophysin-immunoreactive presynaptic terminals was found in the entorhinal cortex and the hippocampal subfields CA1, CA2, CA3 stratum radiatum and CA3 stratum lucidum. The increased immunoreactive presynaptic terminals found in the present study are in accordance with the positive effects of the drugs on spatial learning and memory in young rats (Gschanes & Windisch 1999).

Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 24-month-old rats.

The brain-derived peptidergic drug Cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Positive effects on learning and memory have been demonstrated in various animal models and also in clinical trails. In the present study, the effects of Cerebrolysin and its peptide preparation E021 on the synapse density in the hippocampus, the dentate gyrus and in the entorhinal cortex of 24-month-old rats were investigated. Rats received the drugs or saline for control for 19 consecutive days (2.5 ml/kg per day). Slices of the brains were immunohistochemically stained with anti-synaptophysin, which is a specific marker of presynaptic terminals. Quantification of the synapse density was done by using light microscopy and a computerised image analysing system. Our results clearly showed that the rats benefit from the administration of both drugs, showing an enhancement in the number of synaptophysin-immunostained presynaptic terminals in the entorhinal cortex, the dentate gyrus, and also in the hippocampal subfields CA1, CA2, CA3 stratum lucidum and CA3 stratum radiatum. It can be assumed that these effects are the reason for improved cognitive performances of rats treated with Cerebrolysin and E021.

Early postnatal treatment with peptide preparations influences spatial navigation of young and adult rats.

The brain derived peptidergic drug Cerebrolysin has been found to support the survival of neurons in vitro and in vivo. Positive effects on learning and memory have been demonstrated in various animal models and also in clinical trials. In the present study the effects of early postnatal administration of Cerebrolysin (Cere, 10 mg/ml peptides) or an enriched peptide fraction of Cere (E021, 80.6 mg/ml peptides) were investigated in young, young adult, and old adult rats. Rat pups received the drugs or saline for control on postnatal days 1-7. The animals were tested in the Morris water maze (MWM) either in the 5th week, in the 3rd or the 16th month of life for 6 consecutive days (test days 1-6), eight trials per day. In order to prevent the chance finding of the hidden platform, the rigid underwater platform was replaced by a collapsible island, resting at the bottom of the pool. The platform was raised when the animal stayed in the target area for 2 s. In the young and young adult rats both Cere and E021 treated rats showed shorter escape latencies than saline treated controls on all 6 test days. No significant differences in the swimming speed were evaluated for the young rats, although in 3-month-old drug-tested animals a moderate increase of the swimming speed was investigated. For 16-month-old animals no significant differences in either escape latencies or swimming speed was found. Summarizing, early postnatal application of Cere or E021 improved the spatial learning and memory of young rats and led to long-lasting behavioural effects at least up to 3 months after treatment.

Effects of NGF, b-FGF, and cerebrolysin on water maze performance and on motor activity of rats: short- and long-term study.

The effects of 14-day treatments with nerve growth factor (NGF), basic fibroblast growth factor (b-FGF), or the peptidergic drug Cerebrolysin on postlesion acquisition of a water maze task and on motor activity were evaluated. Rats were tested in the Morris water maze 14 days (early test) and 7 to 8 months (delayed test) after a bilateral lesion of the frontoparietal (sensorimotor) cortex. Only the rats treated with Cerebrolysin performed the water maze task at the level of the nonlesioned controls in the early test. No short-term effect of NGF (6.5 ng/14 days; 38 ng/ml) or b-FGF (17 ng/14 days; 100 ng/ml) treatment was found. The delayed test revealed that water maze performance was restored in rats treated with b-FGF in comparison with intact controls. The data showed that b-FGF can support or initiate processes in the CNS that lead to a delayed functional amelioration and/or compensation for a water maze performance deficit. NGF did not influence the acquisition impairment caused by a sensorimotor cortical lesion. Two-week administration of Cerebrolysin had a time-dependent influence: it attenuated the acquisition deficit and increased the motor activity of rats, both effects declined to the level of lesioned controls within 8 months.

Neurotrophic activities and therapeutic experience with a brain derived peptide preparation.

In spite that the use of naturally occurring neurotrophic factors like NGF, BDNF, CNTF, GDNF and others for treatment of neurodegenerative disorders seems promising because of their pharmacological properties, until now no large scale clinical trials have been published. One of the reasons is that these molecules are unable to penetrate through the blood brain barrier, making invasive application strategies like intracerebroventricular infusion necessary. Another one is the fact that in first clinical studies, several undesirable side-effects like hyperalgesia or weight loss have been reported. Major efforts are now put into development of improved application procedures and in treatment protocols for avoiding the known side-effects. Already 7 years ago it has been demonstrated that Cerebrolysin, a peptidergic drug, produced from purified brain proteins by standardized enzymatic breakdown, containing biologically active peptides, is exerting nerve growth factor like activity on neurons from dorsal root ganglia. Still ongoing investigations are showing growth promoting efficacy of this drug in different neuronal populations from peripheral and central nervous system. The current findings are in accordance with several older publications, enabling now a more clear interpretation of these findings. In addition to the direct neurotrophic effect, the drug also shows clear neuroprotective properties after different types of lesion in vitro and in vivo, resembling the pharmacological activities of naturally occurring nerve growth factors. Neurotrophic and neuroprotective efficacy has been shown with a broad variety of methods in different models and it is remarkable that all biochemical and morphological drug dependent alterations are resulting in improvements of learning and memory. Because of these experimental results, clinical trials using cerebrolysin in Alzheimer's patients have been performed, demonstrating a quick improvement in the overall state of the patients, particularly enhancing the cognitive performance. It is remarkable that these effects are long lasting after cessation of the active treatment procedure. Even 6 months after stop of drug application improvements in AD-patients are detectable. Therefore it is concluded that cerebrolysin is able to induce repair phenomena, resulting in long term stabilization. In contrast to the naturally occurring growth factors, tolerability of this drug is extremely high, without any reports about serious side-effects in these clinical studies.

The influence of Cerebrolysin and E021 on spatial navigation of 24-month-old rats.

In the present study the behavioural effects of Cerebrolysin (Cere), a peptidergic nootropic drug, and E021, the concentrated peptide fraction of Cere, were investigated in 24-month-old rats. Rats passing a pretest to exclude motor- and eye-deficits were treated with either drugs or saline as control (2.5 ml/kg, intraperitoneally i.p.) for 19 days. Animals were tested in a standard Morris water maze on day 16 after pretest for 4 consecutive days (test days 1-4), eight trials per day. No significant differences of escape latency between males and females were found, therefore, results were pooled. Both Cere and E021 treated rats showed significant lower escape latencies than saline treated controls on all four test days (p < 0.01). More pronounced effects of both drugs were found for female rats. Female rats showed no significant differences in motor activity whereas drug treated males swam quicker on test day 1 (Cere p < 0.01: E021 p < 0.05) and day 2 (Cere p < 0.01). In the present experiments it was demonstrated that i.p. administration of both Cere and E021 improves the spatial learning and memory of 24 month-old male and female rats.

Early postnatal stimulation influences passive avoidance behaviour of adult rats.

In this study, the effects of stimulation on either postnatal days 1 to 7 or 21 to 27 on the passive avoidance reaction (PAR) of 3-month-old rats were examined. Animals received tactile or visual stimulation or tactile-visual stimulation for 10 min each day, and were trained at the beginning of the 4th month of life in a step-through apparatus using a footshock of 0.5 mA. Memory retention was measured 24, 48, 72, 96, and 120 h after the acquisition trial. Step-through latencies to enter the dark compartment and the total duration of stay in the illuminated compartment were recorded up to 200 s. Rats that received tactile or a combined tactile-visual stimulation during the 1st postnatal week displayed significantly longer PAR latencies and a longer duration of stay in the illuminated compartment compared to unstimulated control animals. Visual stimulation during the postnatal days 1 to 7 and 21 to 27 resulted in a longer duration of stay in the illuminated compartment. This effect, however, was more pronounced when stimulation was applied during the 1st postnatal week. Rats that received tactile stimulation during the 4th postnatal week showed decreased PAR performance for all measured parameters when compared to animals that received stimulation during the 1st postnatal week. Furthermore, combined tactile-visual stimulation during the 4th postnatal week led to a reduced duration of stay in the illuminated compartment when compared to the stimulation during the 1st postnatal week. These findings can be attributed to the higher degree of plasticity and to a heightened sensitivity to various stimuli in the 1st postnatal week. The results suggest that tactile, visual or combined tactile-visual stimulation have a long-lasting effect on the ability of adult rats to cope with stressful tasks.

Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion.

The effects of the peptidergic nootropic drug Cerebrolysin on spatial memory and motor activity were examined in intact and ischemic rats. Ischemic-hypoxic damage was induced by injection of Na-cyanide followed by bilateral occlusion of common carotid arteries. Immediately afterwards Cerebrolysin or saline was administered, either by continuous intraventricular (i.v.) infusion or by daily intraperitoneal (i.p.) injection. Rats were tested for spatial memory and motor activity in the Morris water maze on days 3 and 4 post-surgery. The best dose of the substance for i.p. administration was known from previous studies. Therefore we had to investigate the dose-response-relationship and tolerability of the drug after i.v. administration in intact rats. Infusion (i.v.) of a high dose of Cerebrolysin (0.57 mg/day) decreased motor activity and spatial memory of intact rats (p < 0.01 and p < 0.05, respectively) but low dose of Cerebrolysin was well tolerated in the intact animals. Ischemia led to deterioration of motor activity in control rats (p < 0.01). Cerebrolysin significantly counteracted deleterious motor changes due to ischemia up to the level of intact controls after both i.v. infusion (0.0057 mg/day) and daily i.p. drug administration (100 mg/kg bw and day) indicating an accelerating recovery after ischemia.

Effects of postnatal stimulation on the passive avoidance behaviour of young rats.

We examined the effects of stimulation on either postnatal days 1-7 or 21-27 on passive avoidance reaction (PAR) of young rats. Animals received tactile or visual stimulation for 10 min each day, and were trained on postnatal day 28 in a step-through apparatus using a footshock of 0.75 mA for 2 s. Retention was tested on five consecutive days beginning on day 29. Memory retention was measured for each rat 24, 48, 72, 96 and 120 h after the acquisition trial. Step-through latencies to enter the dark compartment, time spent in the illuminated compartment and number of crossings of the light beam were recorded up to 200 s. Rats that received tactile or visual stimulation during the 4th postnatal week displayed significantly lower PAR latencies, a shorter stay in the illuminated compartment and a higher number of crossings of the light beam compared to rats treated during the 1st postnatal week. The untreated control group showed a rapid decline of PAR latencies. All experimental groups remained in the illuminated compartment longer and showed PAR latencies well above those of the control group. The differences became more pronounced when visual stimulation in the first postnatal week was used. The number of crossings of the light beam was significantly reduced by the treatment, with the exception of the experimental group stimulated visually in the 4th week. The behavioural changes induced by tactile or visual stimulation have a long-lasting effect in coping with a stressful task.