[Investigation of reinforcing effects and central nervous system effects by drug self-administration procedures].
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Animals↗
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Central nervous system effects of bupivacaine.
The central nervous system and concurrent cardiovascular effects of bupivacaine infusion were studied in cats. It was possible to block cortical E.E.G. desynchronization resulting from a sensory stimulus with bupivacaine. The earliest subcortical change that occurred was rhythmic activity in the amygdala and later in the hippocampus. Occasionally, this activity appeared simultaneously in both these sites. Diazepam pretreatment raised the seizure threshold of bupivacaine. Diazepam was also effective in terminating established seizure activity resulting from bupivacaine. All animals pretreated with diazepam (Valium) or diazepam solvent developed cardiac dysrhythmias durind bupivacaine infusion. The possible clinical significance of the interaction of bupivacaine and diazepam solvent is considered.
Amygdala↗
Antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine.
Altered central nervous system function as indicated by drowsiness and impaired psychomotor performance is often a consequence of the use of traditional antihistamines. Demonstration that newer agents lack these CNS effects requires quantitative and objective measurements that are sensitive enough to assess the psychomotor capabilities required for such activities as driving an automobile. These capabilities include extended attention span, vigilance, visual tracking, rapid information processing, and reaction time. We have used several psychomotor function tests to conduct two investigations assessing the CNS effects of cetirizine. In the first study, 12 healthy, atopic subjects received single oral doses of hydroxyzine 25 mg, cetirizine 10 mg and 20 mg, and placebo in a double-blind, four-way crossover study. Skin-wheal response to intradermal histamine, psychomotor effects, and serum concentrations of each drug were measured for 36 hours after each dose. The CNS effects were measured using critical flash-fusion frequency tests and Stroop word testing. Perceived feelings of drowsiness were measured using a visual analogue scale (VAS). In the second study, 15 healthy subjects received single oral doses of diphenhydramine 50 mg, cetirizine 5 mg, 10 mg, and 20 mg, and placebo in a double-blind, five-way crossover study. Skin-wheal response to intradermal histamine, psychomotor effects, and serum concentrations of each drug were measured for 24 hours after each dose. The CNS effects were measured using digit-symbol substitution testing. "Trails-B" maze tracking, and an analyzer of driving performance that assessed reaction time and vigilance.(ABSTRACT TRUNCATED AT 250 WORDS)
Automobile Driving↗
Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients.
Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study.
Administration, Oral↗
[Combined effects of analeptics on the central nervous system; effect on the size of reflexes].
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Central Nervous System↗
Central nervous system effects of H1-receptor antagonists in the elderly.
BACKGROUND: The potential adverse central nervous system effects of H1-receptor antagonists have not been optimally studied in the elderly. OBJECTIVE: We hypothesized that newer H1-receptor antagonists such as cetirizine and loratadine would cause less central nervous system dysfunction than the older H1-receptor antagonists diphenhydramine and chlorpheniramine in this population, as they do in younger subjects. METHODS: We performed a randomized, double-blind, single-dose, placebo-controlled, 5-way crossover study in 15 healthy elderly subjects (mean age 71 +/- SD 5 years). On study days at least 1 week apart, they received cetirizine 10 mg, loratadine 10 mg, diphenhydramine 50 mg, chlorpheniramine 8 mg, or placebo. Outcome measures, recorded before and 2 to 2.5 hours after dosing were latency of the P300 event-related potential in which increased latency reflects a decreased rate of cognitive processing, visual analogue scale for subjective somnolence, and histamine skin tests for measurement of peripheral H1-blockade. RESULTS: The changes in P300 following each treatment yielded variances that were not equal (P > .05), precluding usual statistical analysis of the means. These variances were ranked: chlorpheniramine > diphenhydramine > loratadine > placebo > cetirizine. The rank of mean differences in the visual analogue scale increase from pre-dose baseline was: diphenhydramine > chlorpheniramine > cetirizine > loratadine > placebo. All H1-receptor antagonists suppressed the histamine-induced wheal and flare significantly compared to baseline. CONCLUSION: In the elderly, the new H1-receptor antagonists cetirizine and loratadine are less likely to cause adverse central nervous system effects than the old H1-antagonists chlorpheniramine or diphenhydramine, but this requires confirmation using additional objective tests of central nervous system function.
Aged↗
[ON THE EFFECT OF DRUGS WITH CENTRAL NERVOUS SYSTEM EFFECT ON THE TOTAL CATECHOLAMINE LEVEL IN WHOLE BLOOD].
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Blood Chemical Analysis↗
Central nervous system effects and visual fatigue in VDT workers.
To assess central nervous system effects and visual fatigue induced by work with visual display terminals (VDT), symptom frequency was assessed and visual evoked potential (VEP), critical flicker fusion (CFF) and near-point distance were measured in 24 female keypunchers before and after 2.5 h of VDT work and in 6 non-VDT-exposed subjects at the same intervals. Each keypuncher had been engaged in data entry for 1-7 (mean, 4) years. After VDT work, the number of complaints of subjective fatigue as well as an objective measure of near-point distance were significantly increased as compared with those before work; also, the N75, P100 and N145 latencies of VEP were significantly prolonged. The change of P100 latency during VDT work was inversely correlated with the number of years worked in data entry. No significant change was seen in any of these tests in the non-VDT-exposed subjects. The changes in N75 latency and subjective fatigue related to drowsiness and dullness in the keypunchers were significantly larger than those in the non-VDT-exposed subjects. The CFF was significantly lower in keypunchers than in non-VDT-exposed subjects in both the first and the second tests. These data suggest that VDT work is associated with impairment of the visual nervous system function, that VEP latencies appear to be a sensitive indicator of visual fatigue, at least transiently, and that CFF appears to be a good parameter for estimations of chronic visual fatigue.
Adolescent↗
A system approach to pharmacodynamics. Input-effect control system analysis of central nervous system effect of alfentanil.
Virtually all biological variables, including those affected by drugs, are subject to adaptive self regulation. In the description of the pharmacodynamics (PD) of drugs, it may be necessary to consider the endogenous control system (ECS) as an integral part of the PD. A PDECS model based on system analysis principles is presented and tested on PD data for alfentanil considering the central nervous system activity quantified by a power spectrum analysis of the electroencephalogram. The model was tested in terms of a proposed relative prediction performance criterion that measures the accuracy of future predictions relative to how well the model describes (fits) the past effect data. A mean value of 80% (standard deviation, 28) for relative prediction performance indicates that the model performs well when challenged by the complex multiple infusion scheme used in the test. The overshoot phenomenon observed in the data is considered by the PDECS model as a ECS-based tolerance phenomenon. The proposed development of tolerance is modeled as a variable gain in the ECS processing that influences the effect. Although the development and loss of tolerance is determined by a single rate constant in the tolerance model, the rates of increase and decrease of tolerance may be substantially different. Contrary to other PD tolerance models, the proposed PDECS approach models the tolerance in terms of an effect deviation from an ECS set point. The intrinsic (no tolerance) effect of the drug is isolated in terms of an open loop (no feedback) effect.
Alfentanil↗
Central nervous system effects of acetate: contribution to the central effects of ethanol.
Acetate, resulting from ethanol metabolism in the liver, is released into the circulation and is utilized in a number of tissues, including the brain. In its metabolism, acetate leads to the production of adenosine, a powerful physiological mediator. We have investigated the effect of acetate on central nervous system (CNS) function in rodents. Sodium acetate in doses resulting in blood concentrations comparable to those attained after the administration of 1 to 2 g/kg ethanol, had significant CNS effects. Both ethanol and acetate produced a dose-dependent impairment of motor coordination. This effect of acetate was fully blocked by the adenosine receptor blocker 8-phenyltheophylline (8PT), whereas the dose-response relationship for ethanol was shifted to the right by about 30%. The inspired concentration of sevoflurane to achieve anesthesia was significantly reduced by both these agents. General anesthesia was potentiated in a dose-dependent fashion by ethanol and by acetate. The effect of acetate on anesthetic requirements was fully blocked by 8PT. The effect of ethanol on sevoflurane anesthetic requirements was inhibited by 22 to 35% by 8PT. Locomotor activity in mice was reduced by acetate in a dose-dependent fashion, an effect that was also fully blocked by 8PT. On the other hand, ethanol at a dose of 1 to 2 g/kg increased locomotor activity. This likely results from a direct stimulatory effect of ethanol, opposed by an inhibitor effect of acetate. The administration of 8PT enhanced the stimulation of locomotor activity induced by ethanol. In conclusion, acetate, a product of ethanol metabolism has significant CNS effects that can either potentiate or antagonize the effects of the ethanol molecule per se.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetates↗
Biological properties of aspartame. I. Evaluation of central nervous system effects.
Aspartame was administered intragastrically to rodents at doses between 10 and 550 times the expected daily human intake to evaluate the effects on central nervous system function. No biologically meaningful effects were observed in either rats or mice following acute administration by the intragastric route. Aspartame administered as 9% of the diet (about 11 g/kg/day) for thirteen weeks to weanling rats altered the learning behavior of male rats. This effect of impaired learning behavior was nearly identical to that observed for an approximately equimolar amount of L-phenylalanine. The learning behavior of the female rats was not altered by either L-phenylalanine or aspartame at these extremely large doses. It was concluded that prolonged dietary ingestion of aspartame at levels approximately 550 times that expected for normal human daily ingestion was necessary to elicit a behavioral deficit.
Analgesics↗
Reversal of central nervous system effects by flumazenil after intravenous conscious sedation with midazolam: report of a multicenter clinical study. The Flumazenil in Intravenous Conscious Sedation with Midazolam Multicenter Study Group I.
Flumazenil, a benzodiazepine antagonist, reverses the residual central nervous system effects of benzodiazepines. In this US double-blind, multicenter study, the efficacy of flumazenil was compared with that of placebo in antagonizing the effects of midazolam, a benzodiazepine used to induce intravenous conscious sedation. The mean dose of flumazenil was 0.7 mg, administered intravenously. At 5 minutes posttreatment, 82% of 131 flumazenil-treated patients, compared with 15% of 65 placebo-treated patients, demonstrated complete reversal of sedation. In 85% of patients who responded to flumazenil, this reversal of sedation was maintained throughout the 180-minute observation period. Psychomotor performance returned to prestudy levels 5 minutes posttreatment in 87% of the flumazenil-treated patients, compared with 28% of the placebo-treated patients. At the doses administered, flumazenil was less effective in reversing midazolam-induced amnesia, with only 60% of patients demonstrating partial recovery of memory. It was, nevertheless, more effective than placebo. Flumazenil was well tolerated. Dizziness (10%) and nausea (9%) were the most frequently reported adverse effects. Results of this study demonstrate that flumazenil antagonizes the central nervous system effects of midazolam after intravenous conscious sedation.
Adolescent↗
Comparison of the central nervous system effects produced by six H1-receptor antagonists.
BACKGROUND: A comprehensive comparative study of the central nervous system (CNS) properties of newer H1-receptor antagonist is needed. OBJECTIVE: Our objective was to investigate the central nervous system effects of a single manufacturer's recommended dose of six H1-receptor antagonists, using appropriate controls. METHODS: Fifteen healthy subjects received astemizole 10 mg, cetirizine 10 mg, ketotifen 2 mg, loratadine 10 mg, terfenadine 60 mg, diphenhydramine 50 mg or placebo. Before and 2-2.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. RESULTS: In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H1-receptor antagonists suppressed the histamine induced weal significantly compared with baseline. CONCLUSIONS: The H1-receptor antagonist tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H1-blockade.
Adolescent↗
The cardiovascular and central nervous system effects in the human of U-62066E. A selective opioid receptor agonist.
The cardiovascular and central nervous system effects of the kappa opioid receptor agonist U-62066E were investigated in ten normal male subjects who received U-62066E or placebo with low or high dose naloxone in a randomized, double blind study. Blood pressure and heart rate in the supine and standing position, plasma adrenaline and noradrenaline, regional Doppler blood velocity indices and psychometric assessments were recorded for 1.25 h before and 6 h following injection. U-62066E caused sedation and dysphoria but no euphoria. Plasma noradrenaline was increased by U62066E when compared with basal levels. This action of U62066E was prevented by high but not low dose naloxone. U-62066E had no significant effect on blood pressure, heart rate or regional blood flow indices in the vessels studied and no effect on plasma adrenaline levels. Since U62066E at a dose known to have marked kappa effects was not found to influence cardiovascular indices our results do not support a major role for kappa opioids in the control of the circulation. However, U62066E may influence noradrenaline release or clearance and cause sedation and psychotomimetic effects.
Adult↗
Central nervous system effects and behavioral interactions with ethanol of centrally administered dilazep and its metabolites in mice.
Dilazep (i.p.), a coronary vasodilator and an uptake inhibitor of adenosine, dose dependently potentiated acute ethanol-induced motor incoordination in mice. In view of peripheral cardiovascular depressive effects of dilazep, the effect of i.c.v. dilazep (25, 50 and 75 micrograms), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (BHPD) (15, 31 and 62 micrograms) and 1-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine (TBPD) (62 and 125 micrograms) on ethanol-induced motor incoordination was studied. Dose-related potentiation of ethanol-induced motor incoordination was noted with dilazep and its metabolites. Whereas dilazep (i.p.) produced no apparent central nervous system (CNS) effects, by i.c.v. route, it caused CNS excitation including tonic-clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridamole, verapamil or N6-(2-phenylisopropyl)-adenosine (R-PIA) administered i.c.v., while potentiating ethanol (i.p.)-induced motor incoordination did not produce seizures. The CNS excitation was minimal with BHPD and none with TBPD. Theophylline pretreatment partially blocked potentiation of ethanol-induced motor incoordination by dilazep and BHPD and not by TBPD. The data suggest dilazep-induced potentiation of ethanol-induced motor incoordination is partially due to central adenosine receptor mechanism and partly due to other yet unknown mechanism(s) and further supported our earlier reports about adenosine involvement in the CNS effects of ethanol. The data also suggest that dilazep (i.c.v.)-induced seizures are due to mechanism(s) other than adenosine uptake inhibition, Ca2+ entry blockade or direct adenosine receptor activation.
Animals↗
No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects.
BACKGROUND: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highly expressed in the small intestine and in the blood-brain barrier. A major function of P-glycoprotein is to limit the absorption and central nervous system exposure of numerous xenobiotics. A genetic polymorphism in the MDR1 gene (C3435T) has been associated with changes in the intestinal expression level and function of P-glycoprotein. The aim of this study was to investigate the effect of this polymorphism on disposition and brain entry of the P-glycoprotein substrate loperamide. METHODS: Healthy white volunteers were genotyped for the MDR1 C3435T polymorphism, and a 16-mg oral dose of loperamide was administered to 8 subjects with the 3435TT genotype and 8 subjects with the 3435CC genotype. Plasma levels of loperamide were determined by liquid chromatography-tandem mass spectrometry. Loperamide-induced respiratory depression was detected as the ventilatory response to carbon dioxide and was used as a measure of central nervous system side effects. RESULTS: We found no significant difference in loperamide pharmacokinetics between individuals homozygous for the C and the T alleles in position 3435 of MDR1, as follows: peak plasma drug concentration, 3164 +/- 1053 pg/mL and 3021 +/- 984 pg/mL; area under the concentration-time curve from 0 to 8 hours, 14414 +/- 4756 pg. h/mL and 14923 +/- 6466 pg. h/mL; and time to peak plasma drug concentration, 3.9 +/- 1.4 hours and 3.9 +/- 2.6 hours for the MDR1 3435CC and 3435TT genotypes, respectively (P >.05, for all parameters). Hypercapnic ventilatory response changed only minimally after ingestion of loperamide (the coefficient of variation during the 0- to 8-hour period was 21% +/- 14% for the sample population), and there was no MDR1 3435 genotype-related effect on respiratory response. Carriers of the 2 major MDR1 haplotypes, MDR1*1 and MDR1*13, did not differ in their response to loperamide. CONCLUSION: There was no association between the MDR1 C3435T variation and plasma levels or central nervous system effects of the P-glycoprotein substrate loperamide in a white study population. The MDR1 haplotype structure was quite variable and supports the use of haplotypes instead of single nucleotide polymorphisms in determining clinical consequences of genetic variation.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Stress interacts with peripheral cholinesterase inhibitors to cause central nervous system effects.
Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to have central cholinesterase inhibition properties under certain conditions (such as when ingested with other chemical compounds or following a high level of stress). Here we tested if stressing rats, using an intermittent 1 hr tailshock protocol, affected the degree of brain acetylcholinesterase (AChE) inhibition caused by a subsequent single injection of PB (2.0 mg/kg) or neostigmine bromide (NB, 0.32 mg/kg), another peripheral carbamate cholinesterase inhibitor. Stressed rats treated with PB had lower levels of AChE activity in the basal forebrain/striatum, but not in other brain areas. Stressed rats treated with NB did not show basal forebrain/striatum AChE activity changes but did show minor reductions of AChE activity in the cortex and cerebellum. These results confirm that prior stress can change the characteristic actions of certain peripherally acting drugs, thus possibly leading to unexpected central nervous system effects. Possible causes for these effects are discussed.
Acetylcholinesterase↗
Glial repair in an insect central nervous system: effects of surgical lesioning.
Surgical lesioning of central nervous connectives in the cockroach (Periplaneta americana (L.], although causing only local glial damage, resulted in complex and prolonged cellular changes. An early response to mechanical disruption was the appearance of granule-containing cells within the damaged perineurium, among adjacent, undamaged, perineurial cells, and between glial processes deep within the connectives. These cells, which were strikingly similar to hemocytes, were clearly involved in phagocytic activity and persisted in the damaged regions for more than a month after lesioning. There was only a slow restoration of organized perineurial glia and re-establishment of the blood-brain barrier, as indicated by the exclusion of an extracellular tracer, ionic lanthanum. These observations contrast with the speedy, ordered repair of the neuroglia observed following selective glial disruption and suggest that undamaged axons and/or the extracellular matrix exert a profound influence on the mechanisms of glial repair.
Animals↗