Serotonergic interhemispheric asymmetry: neurochemical and pharmaco-EEG evidence.

1. Postmortem neurochemical investigations revealed interhemispheric asymmetry in the mediofrontal region of human brain. Significantly higher right hemisphere serotonin metabolite (5HIAA) content as well as increased maximal imipramine binding (IB) were found in the right hemisphere than in the left side. 2. IB did not show a gender difference in the mediofrontal area. However, women had higher IB in the right orbital frontal cortex than did men. 3. In vivo pharmaco-EEG results tend to support the postmortem neurochemical data. Intravenous chlorimipramine resulted in an asymmetric topographic distribution of the P300 auditory evoked potential, peak amplitudes were shifted to the right hemisphere.

Long-term follow-up study with repetitive transcranial magnetic stimulation (rTMS) in Parkinson's disease.

Several studies have claimed the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in Parkinson's disease (PD). The rTMS therapy has to be repeated regularly to achieve a permanent effect but the side effects of long-term administration of low frequency rTMS are not known. Further, there is no information about its influence on the development of Parkinson's disease. Two different groups of patients with PD were compared in a retrospective study for 3 years. The first group (A) was treated with drugs, the second group (B) was treated with drugs + rTMS (1 Hz, 0.6 T, 100 stimuli per day for 7 days using a round coil). rTMS was repeated at least twice each year for 3 years. Symptoms of PD were assessed using the Graded Rating Scale. Although at the onset of the study group B patients had greater disease severity and were receiving higher doses of levodopa, this group (receiving rTMS) showed no deterioration in these parameters, whereas those in group A receiving drugs alone showed a marked deterioration. Hoehn-Yahr (H-Y) stages at the onset of the study and 3 years later were: group A: 1.93 +/- 0.75, 3.03 +/- 1.01; group B: 2.50 +/- 0.83, 2.45 +/- 0.62. The dose of levodopa (mg/day) was at the onset of trial and 3 years later was: group A: 124.4 +/- 144.0, 555.5 +/- 247.2; group B: 287.7 +/- 217.1, 333.4 +/- 181.0. The yearly increment in the scores was: group A: 1.308 +/- 0.307 (P < 0.001), group B: 0.642 +/- 0.389 (P < 0.1). Accordingly, this retrospective study using regularly repeated rTMS with 1 Hz for 7 days, at least twice yearly for 3 years, significantly slowed the development of Parkinson's disease. Unwanted side effects were not observed during the 3 years.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Effect of neonatal beta-endorphin imprinting on sexual behavior and brain serotonin level in adult rats.

A single dose (3 microg) beta-endorphin was administered to newborn female and male rats (hormonal imprinting). In adult age (at 5 months) sexual behavior, steroid hormone binding capacity and brain serotonin content was studied. Females' sexual activity (lordosis quotient) significantly decreased and more animals protested against mounting (ratio of kicking and crying 21/24 vs. 8/24; p < 0.001). Males' sexual activity did not change, however more males were aggressive (4/10 vs. 1/10). Uterine estrogen receptor density significantly increased and affinity decreased. There was no change in the binding capacity of thymic glucocorticoid receptors. In the brain, five regions were studied for serotonin content. There was a gender difference in serotonin level and the intragroup differences were also high. In the endorphin treated males the serotonin level was significantly lower than in the controls. In the endorphin treated females the intragroup scattering has been significantly reduced. Nociceptin content of the cerebrospinal fluid was not changed. The experiments call attention to the possibility of adjustment of sexual and behavioral sphere by the individually different endorphin surge during labor.

Evaluation of some properties of individual bioequivalence (IBE) from replicate-design studies.

BACKGROUND: One of the claimed benefits of the individual bioequivalence (IBE) approach has been that the aggregate regulatory model rewards a test formulation when it has a within-subject variation smaller than the reference product. Hauck et al. [1996] demonstrated that, in the absence of random variations, this property of IBE was due to the tradeoff between the difference of the means and the deviation between the intrasubject variances of the two formulations. The tradeoff was a consequence of the aggregate regulatory model. However, calculations of Endrenyi and Hao [1998] showed that, in the presence of random variations, not only rewards but also penalties can arise due to chance alone. METHODS: A data set of 55 investigations made public by the FDA in 1999 and containing replicate crossover designs was analyzed. Two parameters, AUC and Cmax, were determined in each investigation. RESULTS: The analyses of the FDA data indicate that: rewards and penalties occur at similar frequencies, large rewards and penalties are recorded quite often, and the aggregate IBE model is rather insensitive to the difference between the estimated means and is compatible with the frequent occurrence of large deviations. CONCLUSION: Rewards and penalties, apparently arising from random variations, can affect regulatory decisions on the acceptance of IBE and can lead to incorrect conclusions.

Truncated AUC evaluates effectively the bioequivalence of drugs with long half-lives.

Crossover trials were simulated in order to evaluate whether shortening the duration of bioequivalence trials for drugs with long half-lives would adversely affect the statistical properties of estimated AUC ratios. The trials were simulated under a wide range of assumed kinetic and experimental conditions. The duration of the simulated experiments was gradually shortened and ratios of truncated AUCs were evaluated. In addition, simulations by Martinez and Jackson [1991] were substantially extended. It was demonstrated that the variation of truncated AUCs did not rise, and their bias was negligible when investigations were limited to 2 (and under many conditions to 1) half-lives following drug administration. With large variability of clearance, high limit of quantitation, and/or 2-compartmental models, the observed variation actually often increased when the duration of a study was extended. It was concluded that the assessment of bioequivalence for long half-life drugs would not be adversely affected by limiting the duration of an investigation and, consequently, by using truncated AUCs.

Scaling or wider bioequivalence limits for highly variable drugs and for the special case of C(max).

OBJECTIVE: To illustrate that bioequivalence (BE) can be effectively evaluated for highly variable (HV) drugs and drug products and for the special case of C(max) by using average BE. To demonstrate that either scaling or wider regulatory limits need not result in large observed ratios of the geometric means (GMR) of the 2 drug products. METHODS: Two- and 4-period crossover BE investigations with 24 subjects were simulated. Variabilities of 15, 25 or 35% were assumed in special studies of C(max) and 40% in the general investigations of HV drugs. Acceptance of BE was analyzed in each study by various procedures and regulatory criteria. Under each condition, the percentage of simulated investigations accepting BE was recorded as the simulated GMR was gradually raised from 1.00. RESULTS: Scaled average BE for HV drugs (in both 2- and 4-period studies) and expanding limits for C(max) increased substantially, as expected, the proportion of investigations accepting BE. An additional secondary regulatory criterion constrained the simulated GMR to 1.25 and limited the possibility of large deviations between the mean metrics of the 2 formulations. Acceptance of BE by the composite regulatory expectation never exceeded the acceptances by the separate component criteria. CONCLUSIONS: The sample size required for the evaluation of BE for HV drugs and drug products can be substantially reduced by applying the approach of scaled average BE. The same conclusion is reached from the determination of BE for the C(max) metric by expanding the regulatory limits to 0.75 - 1.33 or even to 0.70 - 1.43. Concerns for observations of high GMR values can be eased by imposing constraints with a secondary regulatory criterion.

[Comparative study of the analgesic effect of Apranax and Cataflam after oral surgical procedures]. / Az Apranax és a Cataflam fájdalomcsillapító hatásának összehasonlító vizsgálata szájsebészeti beavatkozást követóen.

After oral- and maxillo-facial surgical interventions both Apranax and Cataflam proved to be satisfying against pain. Though there is no difference in the kinetics of the effect, we found Apranax more effective to relieve postoperative pain. Besides the fast elimination of pain the medicine significantly mitigate the symptoms of inflammation.

Effect of a single neonatal oxytocin treatment (hormonal imprinting) on the biogenic amine level of the adult rat brain: could oxytocin-induced labor cause pervasive developmental diseases?

Perinatal single-hormone treatment causes hormonal imprinting with lifelong consequences in receptor-binding capacity, hormone production as well as in social and sexual behavior. In the present experiments, newborn rats were treated with a single dose of oxytocin, and the levels of biogenic amines and their metabolites were studied in 8 different brain regions and in the sera when the male and female animals were 4 months old. Both dopaminergic and serotonergic neurotransmission was found to be significantly influenced. The levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole acetic acid metabolites decreased in the hypothalamus and striatum. Dopamine, serotonin, norepinephrine, and 5-hydroxytryptophol levels were hardly altered, and there was no difference in the epinephrine levels. The results show that dopamine and serotonin metabolism of hypothalamus and striatum are deeply and lifelong influenced by a single neonatal oxytocin treatment Oxytocin imprinting resulted in decreased dopamine turnover in the hypothalamus and decreased serotonin turnover in the hypothalamus, medulla oblongata, and striatum of females. As the disturbance of brain dopamine and serotonin system has an important role in the development of pervasive developmental diseases (eg, autism) and neuropsychiatric disorders (eg, schizophrenia), the growing number of oxytocin-induced labor as a causal factor, cannot be omitted.

Effect of neonatal benzpyrene imprinting on the brain serotonin content and nocistatin level in adult male rats.

Single neonatal treatment (imprinting) with 20 microg benzpyrene results in significant increase of the brain serotonin level in the striatum, while in the other four regions (cortex, brainstem, hippocampus, hypothalamus) when measured in adults can be detected. The nocistatin level of cerebrospinal fluid (CSF) significantly decreases, while there is no change in the plasma nocistatin level. The results call attention to the comprehensive imprinting effect of benzpyrene, which in addition to receptorial, hormonal and sexual behavioral disturbances causes lasting differences in the brain serotonin and nocistatin levels, probably influencing mood and pain tolerance.

Effects of extremely low concentrations of hormones on the insulin binding of Tetrahymena.

FITC-insulin binding to previously hormone-treated Tetrahymena was studied by flow cytometry and confocal microscopy. Hormones produced by Tetrahymena were chosen for study and the hormone concentrations were administered between 10(-6) and 10(-21)M for 30 min. Endorphin, serotonin and insulin significantly reduced the hormone binding however histamine did not influence it at all. Endorphin, serotonin and insulin were significantly effective down to 10(-18)M and the effect of insulin and endorphin suggest a similar mechanism. The results call attention to the efficacy of very low hormone concentrations, which can influence the hormone content (earlier experiments) and receptor binding capacity (present study) of a unicellular organism. This seems to be very important, as in wild (natural) conditions the dilution of signaling materials secreted by a water-living protozoan is very high. In addition, the results point to the selectivity of response, as not all of the hormones that deeply influence other physiological indices (e.g. histamine) have an effect on insulin content or insulin receptors.

Prolonged effect of stress (water and food deprivation) at weaning or in adult age on the triiodothyronine and histamine content of immune cells.

We used two days of total water and food deprivation as stress for female rats at weaning (three weeks old) and at adult age (two and a half months old). Triiodothyronine (T3) and histamine content of immune cells (lymphocytes, mast cells and monocyte-macrophage-granulocyte group in peritoneal fluid; lymphocytes, granulocytes and monocytes in blood; and lymphocytes in thymus) were studied three weeks after stress application using specific antibodies for flow cytometry and confocal microscopy. The stress at weaning increased T3 content of thymus lymphocytes. In case of adult T3, there was a cell type independent significant effect of stress, decreasing values in peritoneal fluid and slightly increasing effect in the blood. Histamine content of granulocytes was also significantly elevated. The experiments demonstrate that not only fetal or neonatal stress has long-lasting consequences, but also stress events in later periods of life in cells (organs) that are continuously differentiating. We will go on to discuss the importance of T3 and histamine in connection with stress and immunity.

Algorithms for robust nonlinear regression with heteroscedastic errors.

Nonlinear regression algorithms were compared by Monte-Carlo simulations when the measurement error was dependent on the measured values (heteroscedasticity) and possibly contaminated with outliers. The tested leastsquares (LSQ) algorithms either required user-supplied weights to accommodate heteroscedasticity or the weights were estimated within the procedures. Robust versions of the LSQ algorithms, namely robust iteratively reweighted (IRR) and least absolute value (LAV) regressions, were also considered. The comparisons were based on the efficiency of the estimated parameters and their resistance to outliers. Based on these criteria, among the tested LSQ algorithms, extended least squares (ELSQ) was found to be the most reliable. The IRR versions of these algorithms were slightly more efficient than the LAV versions when there were no outliers but they provided weaker protection to outliers than the LAV variants.

Subject-by-formulation interaction in determinations of individual bioequivalence: bias and prevalence.

PURPOSE: 1. To determine properties of the estimated variance component for the subject-by-formulation interaction (sigma D2) in investigations of individual bioequivalence (IBE), and 2, to evaluate the prevalence of interactions in replicate-design studies published by FDA. METHODS: Four-period crossover studies evaluating IBE were simulated repeatedly. Generally, the true bioequivalence of the two formulations, including sigma D2 = 0, was assumed. sigma D2 was then estimated in a linear mixed-effect model by restricted maximum likelihood (REML). The same method was applied for estimating sigma D2 for the data sets of FDA. RESULTS: 1. sigma D estimated by REML was positively biased. The bias and dispersion of the estimated sigma D increased approximately linearly with the estimated within-subject standard deviation for the reference formulation (sigma WR). Only a small proportion of the estimated sigma D exceeded the estimated sigma WR. 2. Distributions of the estimated sigma D were evaluated. At sigma WR = 0.30, a level of estimated sigma D = 0.15 was exceeded, by random chance, with a probability of about 25%. 3. Importantly, the behaviour of the sigma D2 values estimated from the FDA data sets was similar to that exhibited by the simulated estimates of sigma D2 which were generated under the conditions of true bioequivalence. CONCLUSIONS: 1. sigma D estimated by REML is biased; the bias increases proportionately with the estimated sigma WR. Consequently, exceeding a fixed level of sigma D (e.g., 0.15) does not indicate substantial interaction. 2. The data sets of FDA are compatible with the hypothesis of sigma D2 = 0. Consequently, they do not demonstrate the prevalence of subject-by-formulation interaction. Therefore, it could be sufficient and reasonable to evaluate bioequivalence from 2-period crossover studies.