Encephalotropic and psychotropic effects of intravenous buflomedil in the elderly: double-blind, placebo-controlled pharmaco-EEG and psychometric studies

In a double-blind placebo-controlled study, the encephalotropic and psychotropic properties of intravenously administered buflomedil--a new vasoactive drug--were studied in 10 elderly volunteers in their 60s by means of quantitative EEG and psychometric analyses. At weekly intervals the patients received randomized (latin square design), single, intravenous doses of placebo, 50 mg, 100 mg and 200 mg buflomedil as well as 2000 mg piracetam as reference substance. EEG recordings and the monitoring of blood pressure, heart rate and side-effects were carried out at hours 0, 1, 2, 4, 6 and 8. Psychometric tests were performed at hours 0, 2, 4, 6 and 8. Computer-assisted spectral analysis of the EEG demonstrated that buflomedil exerted a significant effect on the central nervous system (CNS) as compared with placebo, characterized by a decrease of delta and theta, increase of alpha and alpha-adjacent beta activity as well as by an acceleration of the centroid of the alpha activity and also of the total activity. 2 g piracetam induced the same type of changes only at the end of the recording day. These quantitative EEG changes have been previously observed after several antihypoxidotic/nootropic drugs and indicate an improvement in vigilance in the sense of Head. Treatment-efficacy calculations demonstrated that 200 mg buflomedil was the most CNS-effective substance followed by 100 mg and 50 mg buflomedil and 2 g piracetam. Time-efficacy calculations showed that the encephalotropic effects were already marked in the 1st hour after i.v. application, decreased to a low in the 4th hour and subsequently increased again to reach a maximum in the 8th hour. In contrast, 2 g piracetam induced CNS changes which increased from the 1st throughout the 6th hour to show only a slight decline thereafter. The hysteresis between pharmacodynamic and pharmacokinetic findings is discussed. Psychometric investigations demonstrated that after 50 mg buflomedil i.v. there was a significant improvement as compared with placebo in cognitive function based on the Pauli test as well as an increase in correct reactions in the alphabetical reaction test. Doses of 100 mg buflomedil also produced an improvement in the Pauli test, attenuated errors in the reaction time task, improved complex reaction on the Vinnese Determinationsger?t, increased CFF but also errors in the concentration test.(ABSTRACT TRUNCATED AT 400 WORDS)     

Early clinical pharmacological trials with a novel partial benzodiazepine agonist/antagonist Ro 17-1812 using pharmaco-EEG and psychometry

In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of a new partial benzodiazepine agonist Ro 17-1812 were investigated as compared to the pure agonist diazepam utilizing quantitative EEG and psychometric analysis as well as clinical observations. Ten normal volunteers received randomized (latin square) and at weekly intervals single oral doses of placebo, 0.05 mg, 0.1 mg and 0.2 mg Ro 17-1812 and 10 mg diazepam as reference drug. EEG recordings, psychometric tests and evaluation of pulse, blood pressure and side effects were carried out at the hours 0,1,2,3,4, and 6. Computer-assisted spectral-analysis of the EEG demonstrated after 10 mg diazepam a typical "anxiolytic" pharmaco-EEG profile characterized by an increase of beta activity, decrease of alpha activity and acceleration of the centroid of the total activity. Total power tended to decrease while delta activity tended to increase, although only in the resting condition. Ro 17-1812 induced in the vigilance controlled recordings a similar profile thereby exhibiting tranquilizing properties. However, in the resting condition the most consistent change was an increase of delta/theta activity along with a decrease of alpha activity, whereas only in the higher dosage range was beta activity also augmented. These data indicate a selective sedation after the novel partial agonist but are also reminiscent of changes seen after neuroleptic drugs. Dose/treatment efficacy calculations demonstrated 10 mg diazepam as the most CNS-effective drug followed closely by 0.2 mg Ro 17-1812, 0.1 and 0.05 mg while-placebo induced the least changes. Time-efficacy calculations showed a peak effect after 10 mg diazepam in the 1st hour with a gentle decline up to the 4th hour and thereafter again an increase (active metabolites), while the peak of Ro 17-1812 was consistently found in the 2nd hour with a steady decline thereafter as the encephalotropic effect in the 6th hour was less marked than in the 1st hour. Psychometric investigations showed the same time course of both compounds, with the most psychoactivity observed after 0.2 mg Ro 17-1812 and the least after placebo. The fact that the partial agonist induced more decrement in the noopsyche, but specifically in the thymopsyche, of the normal volunteers than the pure agonist may indicate a lower dependency risk of the former than the latter. Evaluation of pulse and blood pressure showed no clinically relevant findings.     

Pharmacokinetic and dynamic studies with a new anxiolytic imidazo-pyridine alpidem utilizing pharmaco-EEG and psychometry

In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic effects of a new imidazo-pyridine derivative, alpidem (SL80.0342) and the 1,4 benzodiazepine lorazepam were investigated utilizing quantitative EEG and psychometric testing. Ten normal volunteers received randomized (latin square) single oral doses of placebo, 25 mg, 50 mg and 100 mg alpidem and 2.5 mg lorazepam at weekly intervals. Blood level sampling, EEG recordings, evaluation of pulse, blood pressure and side-effects were carried out at 0, 1, 2, 4, 6 and 8 hours post drug; psychometric and psychophysiological investigations at the same time periods except for the first hour. Computer-assisted spectral-analysis of the EEG demonstrated an anxiolytic profile after both compounds, characterized by an increase of beta activity, decrease of alpha activity and acceleration of the centroid of the total activity and total beta activity. Total power was attenuated, delta activity augmented and the centroid of the combined delta and theta activities decreased. The latter changes were most pronounced after 2.5 mg lorazepam suggesting it is more sedative than alpidem. Dose/treatment efficacy calculations revealed 2.5 mg lorazepam as the most CNS-active compound, followed by 100 mg, 50 mg and 25 mg alpidem. Based on a multivariate analysis 2.5 mg lorazepam could be differentiated from placebo at all times, 100 mg alpidem in the first, second and fourth hours, 50 mg only in the second hour. Time-efficacy calculations showed a marked CNS effect after alpidem in the first hour with a peak in the second hour, a gentle decline to the fourth hour and thereafter a rapid decline up to the eighth hour. In contrast, 2.5 mg lorazepam showed a slower rise in CNS activity which peaked in the fourth hour and declined slowly thereafter. These pharmacodynamic effects paralleled the blood level course of both compounds, as well as the time-course of psychometric changes. The latter were characterized by a deterioration in psychometer function after 2.5 mg lorazepam, which was less pronounced after 100 mg alpidem, while 50 mg and 25 mg showed no significant difference from placebo. Subjective ratings of mood showed a decrement which was most pronounced after 100 mg alpidem, less so after 50 mg, with no difference from placebo after 25 mg or lorazepam. Finally, there were no significant inter-drug differences with regard to psychophysiological variables.     

EEG-Brain mapping,psychometric and psychophysiological studies on central effects of kavain - a kava plant derivative

In a double-blind, placebo-controlled study the encephalotropic and psychotropic effects of kavain-a synthetic kava plant derivative as compared with clobazam were investigated, utilizing EEG brain mapping, psychometric and psychopysiological analyses. 15 normal volunteers received randomized in weekly intervals single oral doses of placebo, 200 mg, 400 mg and 600 mg kavain as well as 30 mg clobazam as reference compound. EEG recordings, psychometric tests, evaluations of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6 and 8. Brain maps of drug induced pharmaco-EEG changes (pharmaco-EEG maps) demonstrated that kavain exerted a significant action on the human brain function as compared with placebo characterized by a dose-dependent increase of delta, theta and alpha 1 activity while alpha 2, beta activity and the centroid of the total activity decreased. These findings are indicative of a sedative effect which was, however, in type quite different from that of the 1·5 benzodiazepine. The latter produced a decrease of delta, theta, alpha 1 and alpha 2 and an increase of beta activity while the total centroid was accelerated. Interestingly, 200 mg kavain induced with a decrease of delta and beta activity and an increase of alpha activity and of total power also vigilance promoting effects. Psychometric investigations demonstrated also clear differences between the two compounds at the behavioural level. Kavain improved the noopsyche as compared with placebo in all 3 doses as there was a significant improvement in intellectual performance (Pauli test), attention, concentration, reaction time and motor speed (rigidity test), while opposite findings were observed after 30 mg clobazam. In regard to thymopsychic variables such as drive, wakefulness, affectivity, mood, well-being, 200 mg kavain produced an improvement as compared with placebo while 600 mg kavain produced sedation as did 30 mg clobazam. Psychophysiological evaluations resulted in only minimal findings. Time efficacy calculations demonstrated after kavain a pharmacodynamic peak in the 1st to the 2nd hour then a drop and a second peak in the 8th hour while clobazam produced maximal central effects in the 1st hour which declined thereafter to show a second peak in the 6th hour. Topographically, most encephalotropic effects were found after kavain in the frontal, after clobazam in the central and parietal areas. Evaluations of pulse, blood pressure and side effect demonstrated good tolerability of both compounds with 30 mg clobazam producing more sedation than kavain.     

Pharmacodynamics of venlafaxine evaluated by EEG brain mapping, psychometry and psychophysiology.

1. In a double-blind, placebo-controlled study the effects of venlafaxine--a novel nontricyclic compound inhibiting neuronal uptake of serotonin, noradrenaline and to a lesser extent dopamine--were investigated utilizing EEG brain mapping, psychometric and psychophysiological measures. 2. Sixteen healthy volunteers (eight males, eight females) aged 21-36 years received randomized and at weekly intervals single oral doses of placebo, 12.5 mg, 25 mg and 50 mg venlafaxine. EEG recordings, psychometric and psychophysiological tests, and evaluation of pulse, blood pressure and side-effects were carried out at 0, 2, 4, 6, and 8 h. 3. EEG brain mapping demonstrated that venlafaxine exerted a significant action on human brain function as compared with placebo at all three doses, characterized mostly by attenuation of absolute power, increase of relative delta/theta and beta, and decrease of alpha power, as well as by an acceleration of the total centroid fronto-temporally and by its slowing centrally and parietally. These findings are similar to antidepressants such as imipramine. Topographically, drug-induced alterations were most pronounced over both fronto-temporal and the right temporal to temporo-occipital regions. 4. Psychometric and psychophysiological investigations demonstrated significant dose-dependent psychotropic properties of the drug. Multivariate statistics exhibited an improvement of both the noopsyche (e.g. attention, concentration, attention variability, memory, fine motor activity, reaction time performance) and thymopsyche (e.g. drive, wakefulness)) but also significant psychophysiological activation (e.g. in c.f.f., pupillary and skin conductance measures). 5. Time-efficiency calculations showed significant central effects from the 2nd hour onwards, with increasing differences between placebo and treatment up to the 8th hour. Nausea was the most frequent complaint and appeared dose dependent.     

Double-blind, placebo-controlled pharmacodynamic studies with a nutraceutical and a pharmaceutical dose of ademetionine (SAMe) in elderly subjects, utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled crossover study, the effects of S-adenosyl-l-methionine (SAMe) on brain function measures of 12 normal elderly volunteers (6 m/6 f, aged 57-73 years, mean: 61 years) were investigated by means of EEG mapping and psychometry. In random order, the subjects were orally administered a pharmaceutical dose of 1600 mg SAMe, a nutraceutical dose of 400 mg SAMe and placebo, each over a period of 15 days, with wash-out periods of 2 weeks in between. EEG recordings, psychometric tests and evaluations of tolerability and side effects were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 15. Multivariate analysis based on MANOVA/Hotelling T2 tests of quantitative EEG data demonstrated significant central effects of SAMe as compared with placebo after acute, subacute and superimposed drug administration of both the nutraceutical and the pharmaceutical dose. EEG changes induced by SAMe were characterized by an increase in total power, a decrease in absolute and relative power in the delta/theta and slow alpha frequencies, an increase in absolute and relative power in the alpha-2 and beta frequencies as well as an acceleration of the alpha centroid and the centroid of the total power spectrum. The delta/theta and the beta centroid showed variable changes over time. The dominant alpha frequency was accelerated, the absolute and relative power in the dominant alpha frequency attenuated after SAMe as compared with placebo. These acute and subacute pharmaco-EEG findings in elderly subjects are typical of activating antidepressants. Time-efficacy calculations showed that acute oral administration of SAMe in both the nutraceutical and the pharmaceutical dose induced the pharmacodynamic peak effect in the first hour with a subsequent decline. The 3rd and 6th hours still showed a significant encephalotropic effect after the 1600 mg dose. The maximum EEG effect was noted after 2 weeks of oral administration of both 1600 mg/die and 400 mg/die. The superimposed dose induced significant encephalotropic effects in the 3rd hour after 400 mg and in the 3rd and 6th hours after 1600 mg as compared with pre-treatment. Dose-efficacy calculations showed that the pharmaceutical dose of 1600 mg had a more pronounced effect on the CNS than the nutraceutical dose of 400 mg, with both doses being superior to placebo. Psychometric tests concerning noopsychic and thymopsychic measures as well as critical flicker fusion frequency generally demonstrated a lack of differences between SAMe and placebo, which reflects a good tolerability of the drug in elderly subjects. This was corroborated by the findings on side effects, pulse and blood pressure.     

Pharmacokinetic and -dynamic studies with a new anxiolytic, suriclone, utilizing EEG mapping and psychometry.

1. In a double-blind, placebo-controlled, cross-over study, acute pharmacokinetic, neurophysiological and psychotropic effects of suriclone, a new cyclopyrrolone derivative, were investigated and compared with alprazolam. 2. Fifteen normal young volunteers received randomized oral single doses of placebo, 0.1, 0.2 and 0.4 mg suriclone as well as 1 mg alprazolam as reference compound. Investigations were carried out before and 1, 2, 4, 6 and 8 h after drug administration. 3. Pharmacokinetic investigations by radioimmunoassay showed a dose-dependent fast rise of plasma concentrations with a peak at 1 h and a rapid decline thereafter. Both the Cmax and the AUC values exhibited a linear relationship to dose. 4. EEG brain mapping demonstrated significant CNS effects of both compounds, characteristic for tranquillizers (increase of beta, decrease of alpha and increase of delta activity; attenuation of total power and acceleration of the centroid, i.e. centre of gravity frequency). When compared with alprazolam, suriclone exerted less sedative effects. 5. Time-efficacy calculations showed the pharmacodynamic peak effect of suriclone from the 2nd to the 4th hour, and of alprazolam in the 1st hour. Dose-efficacy calculations showed that the most pronounced CNS changes occurred after 1 mg alprazolam, followed by 0.4, 0.2 and 0.1 mg suriclone. 6. Psychometric investigations demonstrated no significant effects after the two lower doses of suriclone, while 0.4 mg and 1 mg alprazolam induced a decrement both in noopsychic and thymopsychic variables seen after higher doses of anxiolytic sedatives. Psychophysiology (critical flicker fusion, pupillometry, and skin conductance measures) pulse rate, systolic and diastolic blood pressure remained unchanged. 7. Psychophysiology (critical flicker fusion, pupillometry and skin conductance measures) showed differential dose-dependent effects. Pulse rate, systolic and diastolic blood pressure remained unchanged. Anxiolytic-characteristic side-effects (tiredness, drowsiness, etc.) occurred predominantly after the highest doses 0.4 mg suriclone and 1 mg alprazolam.     

Proof of antihypoxidotic properties of tenilsetam in man by EEG and psychometric analyses under an experimental hypoxic hypoxidosis

Proof of the protective properties against cerebral hypoxic hypoxidosis of a new potentially nootropic drug, tenilsetam (TEN), were studied as compared with 5 mg co-dergocrine mesylate (CDM) in a double-blnd, placebo-controlled trial. Hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% N₂, equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. They received randomized after an adapation session placebo, 150 mg, 300 mg, and 900 mg TEN and 5 mg CDM. Blood gases, quantitative EEG, and psychometric measures were obtained under normoxic (21% O₂) and hypoxic (9.8% O₂) conditions before as well as 2,4,6, and 8 hr after oral drug administration. Blood gas analysis demonstrated under hypoxia a drop in PO₂ from 91 to 37 mm Hg and in PCO₂ from 38 to 33 mm Hg, while pH increased from 7.41 to 7.47. Under these hypoxic conditions, computer-assisted spectral analysis of the EEG showed an increase of delta/theta, decrease of alpha, and increase of superimposed fast beta activity indicative of deterioration in vigilance. The latter was documented at the behavioral level by deterioration of intellectual and mnestic functions, psychomotor activity, performance in a reaction time task, mood, and wakefulness. Both TEN and CDM attenuated this brain dysfunction, although in a different manner. Whereas TEN induced an increase in alpha and decrease of fast beta activity as compared with placebo, 5 mg CDM attenuated delta/theta and increased alpha-adjacent beta activity. Multivariate analysis based on changes in all EEG-variables exhibited the highest dosage TEN and the reference substance significantly different from placebo. Psychometric data added—despite high variance—further evidence for antihypoxidotic/nootropic properties of both drugs, as psychometric performance under hypoxia deteriorated by 45% after placebo, while after 5 mg CDM, 150 mg, 300 mg, and 900 mg TEN only by 25, 27, 39, and 22%, respectively. Based on changes in all 12 psychometric variables obtained at all times, 900 mg, but also 150 mg TEN as well as 5 mg CDM, were significantly different from placebo. Under normoxic conditions, multivariate analyses did not show any significant differences to placebo, and only singular neurophysiological and behavioral changes were observed.     

Early clinical pharmacological studies with sercloremine—a novel antidepressant—utilizing pharmacokinetic,pharmaco-EEG,and psychometric analyses

Pharmacokinetic and pharmacodynamic properties of sercloremine (CGP 4718A), a novel, selective monoamine oxidase A and serotonin uptake inhibitor, were investigated in healthy volunteers in a double-blind, placebo-controlled, crossover study. The effect of single, oral doses of the drug (50, 100, 200 mg) were, in addition, compared to the effect of 75 mg amitriptyline, which was use as a reference compound. Pharmaco-EEG recordings and plasma level determinations as well as psychometric testings were performed intermittently from O hr up to 8 or 48 hr (pharmacokinetics), respectively. In addition, blood pressure, heart rate, and side effects were recorded. Pharmacokinetic analyses by means of gasliquid chromatography showed a rapid rise in plasma levels of sercloremine with peak concentrations 2 hr after administration. There was a rapid decline thereafter: the distribution and elimination half-lives were estimated to be 4–5 and 14 hr, respectively. Plasma concentrations as well as the area under the curve (AUC) showed clear-cut dose dependency. Computer-assisted spectral analyses of the EEG findings provided evidence of central effects of sercloremine, which were slight but characteristically reminiscent of effect provided by activating antidepressants (“desipramine-type”). Thus, sercloremine produced an increase in total power, alpha activity, and increase of relative and absolute power of dominant frequency, in particular 6 hr after administration. Entirely opposite and remarkably prominent changes were, by contrast, produced by amitriptyline. They were characterized by decrease of relative and absolute power of the dominant frequency and increase of delta and theta activity as well as of superimposed fast activity. Moreover, the centroid of the total activity was slowed down. These changes were previously described as typical for antiderpressants with sedative qualities. Psychometric testing largely confirmed the pharmaco-EEG findings. They indicated vigilance-improving properties of sercloremine which at all three tested doses significantly ameliorated the performance of the volunteers and increased the concentration, attention, cognitive, and mnestic functions. Also, at a dose of 100 mg, there was an improvement of wakefulness, mood, and extroversion as indicated by semantic differential polarity profile records. A vigilance-increasing effect of the drug was also suggested by parallel widening of the pupillary diameter. Consistent deterioration of all subjective and objective varibales tested was observed after administration of amitriptyline. Dose-efficacy calculations indicated that amitriptyline is the most effective centrally active compound, always clearly distinguished from placebo. By contrast, sercloremine was not at all times and in all measures significantly different from placebo. Time-efficacy calculations showed that the peak effect of amitriptyline was situated between 4 and 6 hr after administration, whereas sercloremine exerted maximal pharmacodynamic activity 6–8 hr after dosing. This time lag between the peak plasma concentrations and maximum pharmacodynamic action, described as a “hysteresis loop,” is discussed. Altogether, the results of this study suggest vigilance-increasing properties of sercloremine. The compound was also well tolerated; no cardiovascular or note worthy subjective side effects were recorded.     

Topographic pharmaco-EEG mapping of increasing doses of buspirone and its comparison with diazepam

It has been argued that representative drugs of the main psychopharmacological classes induce similar pharmaco-EEG changes within groups but different changes between groups. The aim of this double-blind, cross-over, placebocontrolled study was to evaluate the effects of single oral doses of buspirone (BUS) 5, 15 and 30 mg in 15 healthy young subjects of both sexes on topographic maps of quantiative pharmaco-EEG, using diazepam (DZP) 10 mg as reference compound. Sixteen lead recordings of three-minute vigilance-controlled EEG (V-EEG) and four-minute resting EEG (R-EEG) were assessed at 0, 1, 2, 4, 6 and 8 hours after drug intake. EOG activity (vertical and horizontal) was also recorded in order to minimize ocular artifacts before applying an automatic artifact rejection method. MANOVA/Hotelling T² maps (multivariate analysis) showed a highly significant differentiation of DZP from placebo from the 1 st until the 8th hour all over the brain. After BUS a clear dose-response was observed with effects being greater and longer lasting with increasing doses, the highest showing a peak effect in the 2nd hour which lasted until the 4th hour, mostly in central regions. Maps of drug-induced pharmaco-EEG changes as compared to placebo-induced alterations (univariate analysis) demonstrated typical ‘anxiolytic pharmaco-EEG patterns’ after DZP, characterized by a decrease of total power, attenuation of alpha activity and augmentation of beta activity, as well as by an increase of the centroid and centroid deviation of the total activity. Furthermore, a decrease of the centroid of the combined delta-theta activity and an increase of the centroid of alpha activity was seen. In contrast, BUS produced an increase of theta activity with an acceleration of the centroid of the combined delta-theta activity, no modification of alpha activity but a slowing down of its centroid and a tendency to reduce beta activity. The centroid of the total activity was also decreased. Although both compounds have proven their ability to reduce anxiety in patients, their different neurophysiological profiles suggest different neurobiological mechanisms of action after acute administration.     

Visualizing central effects of S-adenosyl-L-methionine (SAMe), a natural molecule with antidepressant properties,by pharmaco-EEG mapping

In a double-blind, placebo-controlled, cross-over study, the central effects of the natural molecule S-adenosyl-L-methionine (SAMe), or ademetionine (ADE), used in low doses as a nutraceutical and in higher doses as a pharmaceutical, were investigated by means of EEG mapping and psychometry. Ten young, normal healthy volunteers of both sexes, with a mean age of 25.2+3.9 yr received, in random order, infusions of 800 mg ADE in 250 ml of isotonic solution, and placebo consisting of 250 ml of isotonic solution administered over 30 min for 7 d, with a wash-out period of 3 wk in between. EEG recordings and psychometric tests were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 7. While there were no significant changes in psychometric findings, multivariate analyses of the EEG results based on MANOVA/Hotelling T 2 tests demonstrated significant encephalotropic effects of ADE compared to placebo. ADE-induced changes were characterized by a decrease in total power, an increase in absolute delta power and a decrease in absolute alpha and beta power, further by an increase in relative delta and beta power and a decrease in relative alpha power, a slowing of the delta/theta centroid, an acceleration of the alpha centroid as well as a slowing of the centroid of the total power spectrum. These changes are typical of classical antidepressants of the thymoleptic type such as imipramine and amitriptyline. Time-efficacy calculations demonstrated a significant central effect of ADE in the first hour after the first infusion, declining slowly until the third hour and thereafter steeply until the sixth hour; a further significant effect was after 1 wk of daily infusions and in the third hour after one superimposed infusion on day 7 of subacute treatment. Our pharmaco-EEG findings suggest both inhibitory and excitatory drug effects at the neurophysiological level, underlying the antidepressant properties well-documented in clinical trials.     

Clinical pharmacokinetics of mebikar

Twenty-two patients admitted to the narcological clinic of an industrial enterprise were examined for the clinical effect and pharmacokinetic parameters after intake of a single dose of a Soviet psychotropic drug mebicar. The clinical status was assessed by means of psychometric mapping and concurrent recording of the EEG. The correlation of the pharmacodynamic and pharmacokinetic data can be used for the choice of minimal effective concentrations applied in further calculations of individual dosage regimens.     

On acute and chronic CNS effects of antidepressants in normals: neurophysiological, behavioral and pharmacokinetic studies with pirlindol

In a double-blind placebo-controlled cross-over study the pharmacokinetic and pharmacodynamic properties of acutely and chronically administered prilindol--a new antidepressant possessing both catecholamine-uptake and MAO-inhibitory properties--were investigated in ten normal healthy volunteers. Each subject had a treatment period of two weeks with 3 X 75 mg pirlindol daily and another period of two weeks with placebo. A treatment-free inverval of one week was introduced in between. For comparison purposes a single dosis of 300 mg pirlindol was given as well. Blood level determination, quantitative EEG recordings, psychometric analyses and evaluation of pulse, blood pressure and side effects were carried out at hrs 0, 1, 2, 4, 6, 8 after the administration of one single dosis of 75 mg and 300 mg pirlindol, after one week's and two week's chronic administration of 3 X 75 mg pirlindol, as well as after one additional superimposed dosage of 75 mg and 225 mg on days 8 and 15 of chronic treatment, respectively. Pharmacokinetic analyses by HPLC method with fluorescence detection demonstrated a dose-dependent rapid rise in plasma concentrations peaking in the 1st hr and declining rapidly thereafter (t1/2 TERM = 3 hrs). Computer-assisted spectral analysis of the EEG demonstrated after single doses of 75 mg pirlindol only slight and after 300 mg marked changes in brain activity characterized after the latter by an increase of slow, a decrease of alpha and an increase of beta activity (imipramine-type profile). After one week treatment with 3 X 75 pirlindol, and more so after a superimposed dosage of 75 mg, a significant decrease of delta and increase of alpha activity and slow beta activity occurred (desipramine-type profile). Surprisingly, after two weeks of pirlindol treatment CNS changes were again less marked, suggesting adaptive phenomena. Psychometric analysis demonstrated significant changes after both acute and chronic pirlindol with the latter somewhat superior to the former, as on day 15 a significant improvement of concentration, cognitive function and complex reaction was noted along with a decrease in critical flicker frequency, increase of the total score of the affectivity polarity profile and increase of skin conductance. Time-efficacy calculations demonstrated the pharmacodynamic peak effect in the 4th-6th hr. The time lag between kinetic and dynamic data is discussed. Evaluation of blood pressure, pulse rate and side effects demonstrated good tolerability of pirlindol.     

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.     

Comparative bioavailability studies with a new mixed-micelles solution of diazepam utilizing radioreceptor assay, psychometry and EEG brain mapping

In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic properties of a standard solution of diazepam (DZ) (ValiumR) were compared with those of a novel diazepam mixed-micelles solution (DZ MM) (Valium MMR) both after i.v. and i.m. application utilizing radioreceptor assay, quantitative pharmaco-EEG and brain mapping techniques as well as psychometric and psychophysiological methods. The local tolerance was studied as well. The subjects received randomized and, in weekly intervals, following injections: (1) 10 mg DZ i.v. + placebo i.m.; (2) 10 mg DZ MM i.v. + placebo i.m.; (3) placebo i.v. + 10 mg DZ i.m.; (4) placebo i.v. + 10 mg DZ MM i.m.; (5) placebo i.v. + placebo i.m. Blood sampling, EEG-recordings, psychometric and psychophysiological tests as well as tolerance evaluations were carried out at 0, 1/2, 1, 2, 4, 6 and 8 h. Blood level evaluation demonstrated after i.m. application a significantly shortened tmax, a higher Cmax and generally higher plasma concentrations in the first and second hour following the mixed-micelles solution than the standard formulation, which suggests better absorption of the former than the latter in the muscle. Subsequent to i.v. administration, lower blood levels were observed between 30 min and 2 h after DZ MM than DZ. Power spectral density analysis of the EEG resulted in typical anxiolytic-sedative pharmaco-EEG profiles after all 4 active substances as compared with placebo. However, there were significant inter-drug differences as far as topographic aspects (pharmaco-EEG maps) were concerned. DZ MM i.v. induced significantly more initial but also late delta augmentation, alpha attenuation and centroid slowing than DZ i.v. which suggests more sedative effects at those times. Following i.m. application, a significantly more pronounced delta/theta attenuation, beta augmentation and centroid acceleration after DZ MM than DZ suggested more anxiolytic effects of the novel than the standard formulation. Discriminant analysis of changes in 6 thymopsychic, 12 noopsychic and 17 psychophysiological variables demonstrated the best discrimination of the 4 substances based on thymopsychic effects. Considering the latter, all 4 active compounds differed significantly from placebo, with no inter-drug differences after i.v. application but a marked superiority of the novel mixed-micelles solution over the standard solution after i.m. application. Specifically, DZ MM i.m. induced more desactivation and affect-attenuation than DZ i.m.(ABSTRACT TRUNCATED AT 400 WORDS)     

Classification and assessment of cerebral bioavailability of lopirazepam (D-12524) by quantitative EEG and psychometric analysis

In this double-blind, placebo-controlled study the CNS efficacy and pharmacodynamic properties of 3-hydroxy-5-(o-chlorophenyl)-7-chloro-1,2-dihydro-3H-pyrido[3,2-e]-1,4-diazepin-2-one (lopirazepam, D-12524) was investigated in a group of 10 normal volunteers. Quantitative EEG and psychometric analyses and clinical evaluations were done before as well as 2, 4, 6 and 8 h after oral administration of single doses of placebo, 3 mg, 5 mg and 10 mg lopirazepam and 10 mg prazepam. EEG digital computer period analysis demonstrated dose-dependent changes which are typical of the class of anxiolytics and which started in the 2nd hour, peaked in the 4th hour and lasted after 3 mg, 5 mg and 10 mg up to the 4th, 6th and 8th hour, respectively, 10 mg D-12524 produced an additional augmentation of slow waves indicating sleep-inducing qualities in this dosage. The equipotent dosage to 10 mg prazepam seems to be 5 mg. Psychometric analyses demonstrated an improvement in attention, psychomotor performance, mood and affectivity after 3 mg, opposite changes after 10 mg D-12524. Flickerlight fusion, reaction time, after-image and EAS score were determined as well. Data concerning side effects, pulse rate and blood pressure suggested a good tolerance of the drug.     

吡拉西坦片健康人体药动学和生物等效性研究

目的研究两种吡拉西坦片在健康中国人体的生物等效性.方法20名健康志愿者随机分为试验组和对照组,采用双交叉设计和单剂量口服方式,HPLC法测定血清中吡拉西坦浓度.经DAS2.0统计软件处理,计算主要药代动力学参数,并进行两种片剂的生物等效性评价.结果两种吡拉西坦片剂的t1/2为5.50±1.48、4.29±1.00h,Cmax为21.47±6.27、20.96±5.10mg·L-1,Tmax为O.70±0.46、0.66±0.36 h,AUC0-24h为93.44±16.61、96.67±18.50 mg·h·L-1.受试制剂的相对生物利用度为99.8%±22.7%.结论两种吡拉西坦片剂具有生物等效性.     

Radioelectroencephalographic characterization of tenilsetam (CAS 997), a putative nootropic compound,in the freely behaving rat

Recording, telemetric trandmission, and spectral analysis of field potentials from frontal cortex, hippocampus, striatum, and reticular formation of the rat brain were used to monitor the effect of tenilsetam (CAS 997) and piracetam on the central nervous in delta and alpha₂ power in all brai areas. Dose-dependent decreases in alpha₁ power were seen in the frontal cortex, striatum, and reticular formation, whereas the hippocampal alpha₁ activity increased (100 mg/kg) or remained unaffected. These effects were dose-dependent and lasted for at least 90 min. In the presence of piracetam, changes in brain electrical activity were dominated by an overall decrease in alpha₁ activity and by less pronounced effects on beta₁ activity. The spectral pattern profile induced by tenilsetam was compared to the “fingerprints” of a great number of different drugs from our data base. Some similarities to the action of fluvoxamine and SK&F 38393 point to changes in serotonergic and dopaminergic transmission. The present data show the functional outcome of interactions with different aspects of neurotranmission and suggest that the “nootropic” drug tenilsetam enhances vigilance by shifting the balance of neurotransmission to a status resembling low serotonergic and, at the same time, high dopaminergic activity. These drugs obviously not only improve brain function under pathological conditions but can also affects electrical activity of the intact brain.     

Influence of losigamone on the pharmacokinetics of a combined oral contraceptive in healthy female volunteers

OBJECTIVES: The influence of the new antiepileptic drug losigamone (CAS 112856-44-7/123783-52-8) on the pharmacokinetics of a combined oral contraceptive containing ethinylestradiol (CAS 57-63-6) and levonorgestrel (CAS 797-63-7) was investigated in 16 healthy women. METHODS: This phase I study consisted of 3 periods with an uncontrolled first period and a double-blind, placebo-controlled, cross-over design in the second and third period. All subjects received a single dose of 200 mg losigamone (1 tablet) in period 1 (on day 14) as well as multiple doses of losigamone (3 tablets = 600 mg per day) or placebo for 15 days in periods 2 and 3. During all three periods an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel was given. Single-dose pharmacokinetics was investigated on day 14 of period 1. Multiple-dose pharmacokinetic investigations were performed on day 15 of periods 2 and 3. The samples were assayed to derive pharmacokinetic data of ethinylestradiol and levonorgestrel. In addition, the concentrations of losigamone racemate (AO-33) and its enantiomers AO-242 and AO-294 were determined in these samples. RESULTS: The mean values of the pharmacokinetic parameters AUC and Cmax of ethinylestradiol and levonorgestrel after multiple-dose treatment with losigamone or placebo were quite similar and met the criteria for bioequivalence. The 90% confidence intervals of the log-transformed ratios of the geometric means of the primary pharmacokinetic variables were included in the respective acceptance ranges of 80% to 125% (AUC) and 70% to 143% (Cmax). CONCLUSIONS: The study demonstrated that multiple doses of losigamone did not influence the multiple dose kinetics of ethinylestradiol and levonorgestrel. The single- and multiple-dose kinetics of 200 mg losigamone and its enantiomeres did not differ from each other in a significant way. The combination of losigamone and the combined oral contraceptive was well tolerated and no serious adverse events occurred. It can be stated that the antiepileptic drug losigamone and the combined contraceptive do not interact each others metabolism.