Dose effects of triazolam and scopolamine on metamemory.

The present study compared the acute dose effects of the benzodiazepine triazolam and the anticholinergic scopolamine on metamemory (knowledge and awareness of one’s own memory) in a two-phase paradigm designed to assess effects on both monitoring and control components of metamemory in both semantic (general knowledge) and episodic memory (cued-recall) tasks. Placebo and 2 doses each of triazolam (0.125, 0.25 mg/70 kg, oral) and scopolamine (0.25, 0.50 mg/70 kg, subcutaneous) were administered to 80 healthy volunteers (16 per group) in a double-blind, double-dummy, independent groups design. Both triazolam and scopolamine impaired episodic memory (quantity and accuracy) but not semantic memory. Results suggested that both drugs impaired monitoring as reflected in absolute accuracy measures (impaired calibration in the direction of overconfidence) and control sensitivity (the relationship between confidence and behavior). Overall, the results did not provide evidence for differences between triazolam and scopolamine in memory or metamemory. In addition to the clinical relevance of the observed effects, this study adds to the accumulating body of cognitive psychopharmacological research illustrating the usefulness of drug-induced amnesia as a vehicle to explore memory and metamemory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of triazolam on aggression in men.

To assess the effects of triazolam on human aggression, 46 male participants received either placebo or 0.25 mg triazolam using double-blind procedures. Approximately 60 min after drug ingestion, participants were given the opportunity to administer electric shocks to an increasingly provocative fictitious opponent during a competitive reaction time task. Aggression was defined as the level of shock the participant was willing to administer to the opponent. The results suggest that triazolam consumption was associated with increased levels of aggression. On average, participants who received triazolam set more intense levels of shock for the opponent, and selected the most extreme shock response available more frequently, than participants who received placebo. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional effects on Necker cube adaptation.

If subjects adapt to an unambiguous version of a Necker cube, a subsequent ambiguous cube tends to be seen in the opposing perspective. The present experiment shows that this adaptation effect depends on whether the adapting cube is attended. During the adaptation phase, 12 Ss saw 2 superimposed cubes of opposite perspective and different sizes and colors centered on fixation. Ss detected color changes in line segments that defined either the small or large cube. The perception of the subsequent ambiguous cube depended on which of the adapting cubes was task relevant. This attentional effect showed a strong asymmetry. When Ss attended to the small adapting cube, an aftereffect appropriate to the perspective of the cube was found, but when the large adapting cube was attended, no aftereffect was present. This asymmetry may relate to constraints on the spatial distribution of attention. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute behavioral effects of estazolam and triazolam in non-drug-abusing volunteers.

The present study compared the acute behavioral, participant-rated and observer-rated effects of estazolam and triazolam in 7 healthy, non–drug-abusing humans. Placebo, estazolam (1, 2, and 4 mg), and triazolam (0.125, 0.25, and 0.50 mg) were administered orally in a double-blind, crossover design. Estazolam and triazolam produced orderly dose- and time-related impairment of learning and performance and produced sedative-like participant-rated and observer-rated effects. The absolute magnitude of estazolam's and triazolam's effects at peak effect was comparable across these measures. Triazolam, but not estazolam, impaired immediate and delayed picture recall. The greater effects of triazolam than of estazolam on immediate and delayed picture recall should be viewed cautiously because subtle differences between these drugs in terms of time-to-peak plasma levels may be a confound. Future research should attempt to more thoroughly establish the time–action function of estazolam and triazolam on tasks like picture recall and recognition and determine if the drugs differ at peak effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute and chronic single dose effects of LSD-25 on visual discrimination in rats

The concept of "accident proneness" is frequently discussed and rarely documented. We predicted that children who take more risks as judged by their behavior in gym class, or who have more stressful life changes as determined by their score on a Social Readjustment Rating Questionnaire (SRRQ), would be more likely to injure themselves. 103 junior high school boys were rated for these factors, and then followed for injuries by weekly telephone calls for five months. Boys having high SRRQ scores had significantly more accidents than those with low scores; risk-taking levels were not predictive. In this study, children undergoing stressful changes in their lives were more susceptible to accidents.     

The assessment of residual effects of a single dose of diazepam on visually-defined EEG patterns

Patients with medically intractable trigeminal neuralgia characterized by paroxysmal, triggered, trigeminally distributed pain are excellent candidates for neurosurgical intervention, which can not only relieve the pain of trigeminal neuralgia, but also eliminate the unpleasant side effects of medicines used to treat it. The two major neurosurgical choices are percutaneous denervation and microvascular decompression (MVD). Percutaneous denervation is done best when the surgeon has available radiofrequency and glycerol and uses one, the other, or both depending on technical circumstances that pertain to each patient. The percutaneous denervation is less likely than MVD to cause death, stroke, facial weakness, or hearing loss, but more likely to be associated with recurrence or dysesthesias. Patients with multiple sclerosis, medical illness, or who are elderly are much better candidates for percutaneous denervation. For any patient, a number of other factors also must be considered before deciding on a particular procedure. These include response to previous interventions, ability to tolerate carbamazepine, risk tolerance for various complications, preference regarding duration of hospital stay and postoperative recovery, presence of pain outside the trigeminal distribution, and findings on a high resolution magnetic resonance imaging (MRI) scan.     

Adverse effects of a single dose of (+)-sotalol in patients with mild stable asthma

The case history of a 25-year-old man suffering from idiopathic alveolar proteinosis is described. The patient showed a prolonged stable mild disease and a distinct suppressive phenotypic profile of BALF lymphocytes. Specifically, a low T4/T8 ratio and a high percentage of CD11b+ T8 lymphocytes was found. Correlations with disease expression are made.     

Dose effects of triazolam and alcohol on cognitive performance in healthy volunteers.

Benzodiazepines and alcohol are widely used psychoactive substances that have performance-impairing effects. Research suggests that the impairment profiles for benzodiazepines and alcohol differ, although few cognitive psychopharmacological studies have directly compared these drugs. This double-blind, double-dummy, placebo-controlled, repeated measures study directly compared the acute dose effects of triazolam (0.125, 0.25 mg/70 kg) and alcohol (0.40, 0.80 g/kg) in 20 social drinkers. At doses that produced comparable psychomotor impairment, triazolam was more likely to impair several objective measures of cognitive performance (e.g., episodic memory, divided attention) and to slow performance across several measures. However, only alcohol impaired accuracy on the digit symbol substitution and semantic memory tasks. In addition to objective measures, both drugs impaired awareness of performance impairments (i.e., metacognition) such that participants overestimated impairment, and the magnitude of this effect was generally larger for alcohol. Only triazolam impaired other measures of metacognition (e.g., error detection on a choice reaction time task). Future research might examine the clinical implications of the performance impairments reported here given the widespread use of benzodiazepines and alcohol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Grapefruit juice does not enhance the effects of midazolam and triazolam in man

OBJECTIVES: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam (Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme. METHODS: In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo groups receiving water or Gra. The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake. Study II was similar, but the post-treatment tests were at 45 and 90 min, and the active drugs used were 0.250 mg Trz, GraTrz, and Mid 10 mg. In the crossover Study III, 6 subjects took Mid 10 mg alone and with Gra (GraMid) and 750 mg erythromycin (EryMid). Performance tests were made and blood was sampled before and 30, 60 and 90 min after intake. Midazolam and its active metabolite alpha-OH-midazolam were assayed by gas chromatography (GC) and radioreceptor assay (RRA). RESULTS: In Study I, both Mid and GraMid impaired digit symbol substitution (DSS), letter cancellation (LC) and flicker fusion (CFF) at 90 min. GraMid had more effect (P < 0.05) than Mid on the DSS performance. Mid caused drowsiness at 30 and 90 min. Both Mid and GraMid caused clumsiness and a feeling of impaired performance at 90 min. In Study II, the active drugs impaired objective test performances (DSS, LC, CFF) at 90 min, without having a clear subjective effect. In Study III, Mid, EryMid and GraMid impaired performance in the DSS, LC and CFF tests. EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min. Mean values of plasma midazolam (and alpha-OH-midazolam) at 30, 60, 90 and 120 min after Mid 10 mg were 68(19), 61(19), 43(14) and 42(12) micrograms.l-1. The corresponding values after EryMid were 164(14), 137(13), 104(10) and 89(10) micrograms.l-1, and after GraMid 60(12), 69(16), 61(15) and 57 (14) micrograms.l-1. CONCLUSIONS: The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects.     

Hemodynamic effects of spinal anesthesia in the elderly: single dose versus titration through a catheter

Protective immunity against infection with Mycobacterium tuberculosis is imparted by T cells rather than antibodies, but B cells can play a role as antigen-presenting cells and in granuloma formation. We re-evaluated the role of B cells in the course of tuberculous infection in mu-chain knock-out (Ig-) mice. Surprisingly, the organs of M. tuberculosis-infected Ig- mice were found to have three- to eight-fold elevated counts of viable bacilli compared with normal littermates at 3-6 weeks post-infection. Splenic interferon-gamma responses to whole antigen were unimpaired, whilst proliferation to certain mycobacterial peptides was found to be diminished. However, bacille Calmette-Guérin (BCG) vaccination significantly reduced the infection in Ig- mice. The mechanisms by which B cells can influence primary tuberculous infection need further study.     

Attentional control of spatial scale: effects on self-organized motion patterns

Prior to the presentation of a test stimulus, subjects' attentional state was either narrowly focused on a particular location or broadly spread over a large spatial region. In previous studies, it was found that broadly spread attention enhances the sensitivity of relatively large spatial filters (increasing the perceiver's spatial scale), thereby diminishing spatial resolution and enhancing sensitivity to global stimulus structure. In this study it is shown that attentional spread also affects the self-organization of unidirectional versus oscillatory motion patterns for the directionally ambiguous, counterphase presentation of rows of evenly-spaced visual elements (lines segments; dots); i.e. qualitatively different motion patterns can be formed for the same stimulus at different spatial scales. Although the degree to which attention is spread along a spatial axis can be controlled by the perceiver, the effects of spread attention are not limited to a single axis. These results, as well as previously observed effects of attentional spread on spatial resolution, are accounted for by a neural model involving large, foveally-centered receptive fields with co-operatively interacting subunits (probably at the level of MST or higher).     

Influence of renal failure on the pharmacokinetics and neuromuscular effects of a single dose of rapacuronium bromide

Neurotransmitter transporters are involved in termination of the synaptic neurotransmission and are implicated as the sites of action of antidepressant medicines and illicit drugs. In addition to their function in neurotransmission, neurotransmitter transporters play a key role in neuroregulation and brain development. In this report, the developmental distribution of the "orphan" transporter NTT4, whose substrate has not yet been shown, is described. Immunohistochemical studies have previously shown NTT4 to be specifically and widely localized to the central nervous system. In this report, the distribution of NTT4 in brain areas enriched in glutamatergic and gamma-aminobutyric acid-ergic innervations is further substantiated. NTT4 is detected beginning at E18 in various parts of the rat brain, including the cerebral cortex, fimbria hippocampi, fornix, lateral lemniscus, anterior commissure, and spinal cord. At E18, strong immunoreactivity of NTT4 is observed in the cortical subplate and marginal layers that later develops into the fimbria hippocampi, and at P22, the expression of NTT4 in the hippocampal formation reaches the mature form. The expression of NTT4 in the spinal cord begins at E18 in the ventral white matter. Heavy staining for NTT4 is observed in the substantia nigra since birth and through all time points examined. Transient immunoreactivity is observed in the inferior colliculus, reaching maximal expression at P10, whereas the superior colliculus commences to express NTT4 only after this time point. The globus pallidus is highly stained after birth, and the caudate putamen shows strong staining for NTT4 only at P22. In the adult rat brain, NTT4 is strongly expressed in the olfactory bulb, cerebral cortex, striatum, hippocampus, thalamus, substantia nigra, pontine nucleus, cerebellum, and spinal cord. The developmental distribution of NTT4 suggests involvement in central nervous system maturation.     

The effects of age and gender on the single dose pharmacokinetics of avitriptan administered to healthy volunteers

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150-mg capsule after a 10-hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N-desmethyl avitriptan (ND048), O-desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP). Urine samples were analyzed for only avitriptan and MPP. Avitriptan was well tolerated in all four groups. The drug was rapidly absorbed with a median time to maximum plasma concentration (tmax) between 0.5 and 1.5 hours. No significant gender-related differences were found in the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC0-infinity) of avitriptan. Renal clearance of avitriptan was significantly smaller in young women compared with young men, but this is clinically not relevant because only 2% to 3% of the total dose is excreted unchanged. Compared with the young volunteers, mean Cmax was approximately 50% higher in the elderly but there was no difference in the AUC0-infinity between the 2 age groups. Plasma concentrations of ND048, OD048, and MPP were each 50 to 100 fold lower than those of avitriptan. Hence some age- and gender-related differences found in the pharmacokinetics of avitriptan metabolites are probably not relevant in the assessment of overall safety and efficacy of avitriptan. Based on the pharmacokinetics and tolerability, no age or gender-related dose adjustment is necessary for avitriptan.     

Delayed Attentional Engagement in the Attentional Blink.

Observers often miss the 2nd of 2 visual targets (first target [T1] and second target [T2]) when these targets are presented closely in time; the attentional blink (AB). The authors hypothesized that the AB occurs because the attentional response to T2 is delayed by T1 processing, causing T2 to lose a competition for attention to the item that follows it. The authors investigated this hypothesis by determining whether the AB is attenuated when T2 is precued. The results from 4 experiments showed that the duration and magnitude of the AB were substantially reduced when T2 was precued. The observed improvement in T2 report did not occur at the expense of T1 report, suggesting that processing of T1 was already completed or was at least protected when the cue was presented. The authors conclude that, during the AB, there is a delay between detection and the selection of target candidates for consolidation in short-term memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5–15.0 mg), triazolam (0.0625–0.3750 mg), pentobarbital (25–150 mg), caffeine (100–600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Citalopram: differential sleep/wake and EEG power spectrum effects after single dose and chronic administration

The sleep/wake effects of the selective serotonin re-uptake inhibitor citalopram were studied in both a single-dose study with three dose levels (0.5, 2.0 and 5.0 mg/kg), and a 5-week chronic administration study (15 mg/kg/24 h). Single doses of citalopram resulted in a dose-dependent inhibition of rapid eye movement (REM) sleep. After chronic citalopram treatment there was a sustained REM sleep inhibition. Single doses of citalopram resulted in only minor changes in non-REM (NREM) sleep as well as in NREM EEG power spectral density. Chronic administration resulted in a major shift from SWS-2 to SWS-1. The observed corresponding changes in EEG power density were regional. A 30 to 40 percent reduction of power density in the 0.5-15 Hz range in the fronto-parietal EEG derivation was seen for the whole 8-h registration period. In the fronto-frontal EEG derivation only minor changes were seen. A decreasing trend in NREM sleep power density between 0.5 and 7 Hz, usually seen during the course of the light period, was not observed in the chronic condition, but was seen in control and single-dose condition, suggesting altered diurnal distribution of slow wave activity in the chronic condition. The data indicate that acute and chronic administration of citalopram shows clear differences in sleep effect, which may be caused by alteration of serotonergic transmission, and may be related to the antidepressant effect.     

Effect of cholestyramine resin on single dose valproate pharmacokinetics

Cholestyramine, a nonabsorbable anion exchange resin, has been reported to bind concomitantly administered drugs and decrease their bioavailability. The objective of the study was to determine the effect of cholestyramine on the plasma concentrations of valproic acid (VPA) following concurrent and staggered (VPA 3 hours before cholestyramine) dosing. Six healthy volunteers participated in an open-label, 3-way crossover study. In each phase fasting subjects received 250 mg of VPA followed by serial blood sampling for VPA plasma concentrations over a 37-hour period. In the concurrent and staggered phase the subjects received 4 g of cholestyramine (CHOL) twice daily 24 hours prior to and following the VPA dose. During the concurrent phase the coadministration of CHOL resulted in a decrease (p < 0.05) in the area under the curve (AUC) for VPA compared to VPA alone (415.2 +/- 113.2 mg*hr/l vs 489.2 +/- 153.0 mg*hr/l, respectively). When the same dose of each drug was administered 3 hours apart, the AUC for VPA (454.8 +/- 123.1 mg*hr/l) was not significantly decreased when compared to VPA alone (489.2 +/- 153.0 mg*hr/l). Also, the bioavailability relative to VPA alone was 86.2% +/- 7.1 for the concurrent phase and 95.3% +/- 13.6 for the staggered phase. Based on the AUC of VPA concurrent administration of CHOL significantly decreases VPA absorption and separating the doses of the 2 drugs by 3 hours may lessen the interaction.     

Use of single dose low-molecular-weight heparin in long hemodialysis

BACKGROUND AND OBJECTIVES: Granuloma Inguinale (GI) is an endemic sexually transmitted disease (STD) in India. With increasing prevalence of human immunodeficiency virus (HIV) among patients with STD at a clinic in Mumbai, a study was conducted to determine clinico-epidemiologic features of GI and HIV. GOAL: To determine possible interaction between GI and HIV. STUDY DESIGN: Prospective follow-up of 21 consecutive cases (GI in HIV-seropositive individuals) and 29 controls (GI in HIV-seronegative individuals) to determine time to heal. All cases and controls received a standard treatment regimen of erythromycin, 2 g po daily, under supervision until healing occurred. RESULTS: Although GI ulcers at recruitment were not significantly larger among HIV-seropositive individuals as compared with those seen among HIV-seronegative individuals (mean size 4.4 cm2 vs. 3.6 sq2; odds ratio [OR] 1.22, confidence interval [CI] .95, 0.63, 2.40; p = 0.52), the former took longer time to heal completely (mean 25.7 days vs. 16.8 days; OR 1.82, CI .95, 0.99, 3.36; p = 0.03) and tended to produce greater tissue destruction (as included in results). CONCLUSION: These findings are important because slow-healing GI ulcers with underlying HIV infection, which may be caused by their interaction, will lead to increased transmission of both the infections.     

Time of peak drug concentration after a single dose and a dose at steady state

The time of peak concentration after administration of oral drug is an often quoted and used pharmacokinetic parameter. It is not well appreciated, however, that the peak times after a single dose and a dose at steady state during a multiple administration regimen can differ significantly. This article derives the mathematical relationships that determine how a peak time at steady state differs from that after a single or first dose. These relationships are then evaluated using three different approaches: 1) graphic simulations of time courses of drug concentration for three hypothetical drugs; 2) comparisons of predicted and observed peak times using examples from the literature; and 3) comparisons of predicted and simulated peak times based on different sampling schedules for three hypothetical drugs. The key finding is that peak times after a dose at steady state can occur considerably earlier after administration than after a single dose. However, the manner by which peak times are usually determined, that is, the sampling time corresponding to the highest measured drug concentration, imposes significant limitations on the usefulness of this parameter.