Topographical analysis of the EEG effects of a subconvulsive dose of lidocaine in healthy volunteers

BACKGROUND: The purpose of the present study was to assess the effects of intravenous lidocaine on spatial changes of electroencephalographic power and on psychomotoric status in conscious volunteers. METHODS: In 11 healthy volunteers lidocaine (2-min bolus, 100 mg; 15 min infusion, 40 micrograms.kg-1.min-1) or placebo were given intravenously in a randomized, single-blinded, two-way crossover study. Haemodynamics and lidocaine plasma concentrations were measured at baseline and within a period of 30 min following bolus injection. Vigilance and emotional status were tested using visual analogue scales (VAS). Toxic CNS effects were evaluated by a questionnaire. The raw EEG (17 leads, reference Cz) and computed power spectra were continuously recorded. RESULTS: The chosen lidocaine dosage led to nearly constant plasma concentrations (unbound lidocaine 2.5 min and 15 min after bolus 0.36 +/- 0.14 microgram/ml and 0.30 +/- 0.06 microgram/ml, respectively [mean +/- SD]). The placebo caused no symptoms, changes in VAS-scores or EEG-parameters. Lidocaine induced pronounced subjective symptoms and significant increases in delta activity for 15 min, most dominant at the frontotemporal and occipital leads (max. +219% O1). Frontal and occipital beta 1 and beta 2 power (max. +131% and +124% at O1, respectively) was immediately increased after the bolus injection. No EEG changes occurred at central region Cz, and no interhemispheric EEG differences were noted. Theta, alpha 1, and alpha 2 power remained unchanged. CONCLUSION: The current data demonstrate simultaneous changes in psychomotoric status as well as delta and beta spectral power during lidocaine infusion. These data could be an indication that the pronounced frontotemporal and occipital EEG changes are the electroencephalographic expression of subjective sensations.     

EEG pharmacodynamics upon single administration of seduxen in healthy volunteers

We have examined the type I collagen protein, RNA, and cDNA of 2 children with moderately severe (type IV) osteogenesis imperfecta (OI). They have in common a non-lethal form of OI with ambulatory potential, overmodification of type I collagen protein, and a substitution of serine for glycine in the collagen chain produced by one alpha 1(I) allele. The first child (Marini et al.: J Biol Chem 264:11893-11900, 1989) is now 7 years old, with the height of a 3-year-old. Her course includes significant remodeling of lower long bones and 4 femur fractures. She walks independently. A mishmatch was detected in her alpha 1(I) mRNA using RNA/RNA hybrids; it was demonstrated to be due to a G-->A point mutation in one allele of alpha 1(I), resulting in the substitution of serine for glycine 832. The second child is now 6 1/2 years old, with the height of 1 1/2-year-old. Her history includes significant bowing of femurs and tibias, 6 femur fractures, S-curve scoliosis, compression of all lumbar vertebrae, and limited short-distance walking with braces. Her alpha 1(I) mRNA has also been studied by RNA hybrid analysis; there is a single G-->A change in one alpha 1(I) allele causing the substitution of serine for gly 352. Both children have moderately severe OI. However, the serine substitution at gly 352 is associated with a more severe phenotype then is the serine substitution at gly 832. Compared to substitutions described in other cases of OI, the serine 352 is located in the middle of a cluster of cysteine substitutions associated with non-lethal OI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Establishment of a diazepam preference in human volunteers following a differential-conditioning history of placebo versus diazepam choice.

This study examined whether preference for a drug (diazepam or placebo) could be switched using conditioning procedures. During the first 4 sessions of Phase 1, 6 participants received 5mg of diazepam or placebo under double-blind conditions. During the remaining 5 sessions of Phase 1, participants selected the drug they wished to receive. The first 4 sessions of Phase 2 were a replication of Phase 1, except that following ingestion of the drug, participants completed a computer task for which they could earn money. Payment for the computer task was lowest following ingestion of the drug they preferred in Phase 1 and highest following the drug they had avoided. Preference was reassessed during the last 5 sessions of Phase 2. Five of the participants preferred placebo in Phase 1 but diazepam in Phase 2. Subjective responses to the two drugs also changed across the 2 phases. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers

The bioavailabilities and bioequivalences of single 200-mg doses of itraconazole solution and two capsule formulations were evaluated in a crossover study of 30 male volunteers. The two capsule formulations were bioequivalent. The bioavailabilities of the solutions itraconazole and hydroxyitraconazole were 30 to 33% and 35 to 37% greater, respectively, than those of either capsule. However, the maximum concentrations of the drug in plasma (Cmax), the times to Cmax, and the terminal half-lives were comparable for all three formulations. These data indicate that the bioavailabilities of itraconazole and hydroxyitraconazole are enhanced when administered as an oral solution instead of capsules.     

Memory and psychomotor effects of oxcarbazepine in healthy human volunteers

Cognitive and psychomotor impairments can be unwanted adverse effects of antiepileptic drugs. The present double-blind, cross-over study with healthy volunteers was designed to assess the effects of two doses of oxcarbazepine (OXCZ) (150 mg b.i.d.; 300 mg b.i.d.) and a placebo, each given over a two week period. Twelve subjects completed a battery of tests before and 4 h after morning doses on days 1, 8 and 15. Results of objective tests indicated that OXCZ improved performance on a focussed attention task and increased manual writing speed. Subjective ratings showed OXCZ increased feelings of altertness, clear-headedness and quickwittedness. OXCZ had no effect on the range of long-term memory processes assessed in this study. It is concluded that at the doses employed, OXCZ has a slightly stimulant effect on some aspects of psychomotor functioning.     

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)     

The effects of transnasal butorphanol on mood and psychomotor functioning in healthy volunteers

Transnasal butorphanol is effective in relieving migraine and postoperative pain. The extent to which this drug preparation impacts on cognitive and psychomotor performance, as well as mood, has not been examined. Accordingly, the cognitive and psychomotor, subjective, and physiological effects of two clinically relevant doses of transnasal butorphanol (1 and 2 mg) were compared to that of placebo, and a common analgesic drug combination given for pain relief in ambulatory settings, 600 mg of acetaminophen and 60 mg of codeine, in healthy volunteers (n = 10). The larger transnasal butorphanol dose impaired psychomotor performance for up to 2 h, and produced subjective effects for up to 3 h. The smaller dose had no psychomotor-impairing effects, but had subjective effects (including increased ratings of "sleepy"). All three active drug conditions including miosis. These laboratory results suggest that patients should use caution when using the 1-mg dose of transnasal butorphanol, and should curtail certain activities if they administer the 2-mg dose of transnasal butorphanol for analgesia.     

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.     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Psychotherapy research with children is based mainly on adult methodologies. Common issues include bias in recruitment of subjects, demographics, developmental concerns, and control group considerations. The advantages and drawbacks of various types of control groups, such as wait-list controls, and placebo conditions are discussed along with ethical issues. Instrument choice, validity and reliability, and standardization of procedures in conducting research are addressed. Finally, the therapist as a variable is reviewed, including selection and assignment of therapists, and therapist bias.     

Effects of the antimigraine compound zolmitriptan (''Zomig'') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Posterior lenticonus is a protrusion of the posterior capsule and cortex into the vitreous. The etiology is widely debated because of the rare nature of the condition. Lenticonus can present with concurrent ocular conditions, which can disrupt normal visual development. Currently, the only treatment option for posterior lenticonus is lensectomy, which may still have a reduced chance of visual success secondary to the associated disease. Although strabismus and amblyopia are commonly associated, keratoconus has not previously been reported with unilateral posterior lenticonus. Considering treatment of the associated condition may allow the patient to delay or forego surgical intervention.     

Immunological and trophical effects of Saccharomyces boulardii on the small intestine in healthy human volunteers

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.     

Effect of terbinafine on theophylline pharmacokinetics in healthy volunteers

Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P = 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.     

Cold water immersion modulates the reinforcing effects of nitrous oxide in healthy volunteers.

The purpose of this study was to determine if a contextual variable manipulation, water temperature of a bath in which a forearm was immersed, would modulate the reinforcing effects of nitrous oxide (N?O) in healthy volunteers (N?=?12). Each of 2 separate choice experiments consisted of a lukewarm water session and a cold water session. Each session consisted of 3 trials: The 1st 2 were sampling trials in which participants inhaled either 100% oxygen or 40% N?0 for 25 min, and the last trial was a 25-min choice trial, in which participants chose between the 2 agents. In each of the 3 trials, participants immersed their forearm in either ice-cold or lukewarm water for 3 min. A variant of the McNemar test revealed that participants were more likely to choose N?O on cold water sessions than on warm water sessions. The authors conclude that N?O was more reinforcing when participants forearms were immersed in ice-cold water than when immersed in lukewarm water. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.     

A comparative trial of recombinant interferon alpha 2A versus alpha 2 beta on myelosuppression in healthy adult volunteers

BACKGROUND/AIMS: Recombinant interferon (r-IFN) is an antiviral agent used to treat patients with chronic viral hepatitis patients. Unfortunately, the use is often limited due to its myelosuppressive properties. Currently, there are two forms of r-IFN commercially available: r-IFN alpha-2a and rIFN alpha-2b. Although both are thought to be equally effective, a comparative study of their myelosuppressive properties has not been undertaken. MATERIALS AND METHODS: In the present study, three groups of healthy adult volunteers (n = 6/group) were randomized to receive a two week course of either r-IFN alpha-2a or r-IFN alpha-2b (5 million units, subcutaneously, thrice weekly) or no treatment. All subjects were then followed for an additional two week post treatment; observation period. RESULTS: The results of the study revealed that both forms of r-IFN alpha caused a significant and similar decrease in white blood cell counts (maximum declines of 37.9 +/- 6.8% for alpha-2a and 39.5 +/- 6.0% for alpha-2b at day 4) and platelet counts (maximum declines of 19.5 +/- 8.6% for alpha-2a and 20.2 +/- 8.4% for alpha-2b at day 2) from baseline values. Following discontinuation of therapy, white blood cell and platelet counts returned to pretreatment levels. Hemoglobin levels remained unchanged throughout the study period. CONCLUSION: The results of this study indicate that r-IFN alpha causes a prompt and significant decrease in white blood cell and platelet counts. However, no differences exist between r-IFN alpha-2a and r-IFN alpha-2b in terms of their myelosuppressive properties in humans.     

Effects of low-dose morphine on gastric emptying in healthy volunteers

BACKGROUND: Type 2 diabetes mellitus is a major and increasing cause of morbidity and early mortality among the Aboriginal population of northern Australia. Due to differing social, dietary and probably metabolic factors, management needs differ from the mainstream Australian diabetic population. OBJECTIVE: This paper concentrates on the options for oral therapy in the control of glycaemia, taking into account various current guidelines and recent trials of oral antihyperglycaemic therapy, and the specific metabolic and clinical associations with type 2 diabetes mellitus in this population. DISCUSSION: In the abscence of specific contraindications, and in variance with some present guidelines, the evidence suggests that initial therapy with metformin rather than the sulphonylureas is likely to provide greater clinical benefit, and have a greater margin of safety.     

Effects of lorazepam on film-induced differentiated emotions in healthy volunteers

We studied the effects of lorazepam, a benzodiazepine, on differentiated emotions in healthy volunteers. In order to induce differentiated emotions, film excerpts were selected on the basis of the type of emotion they induced (fear, anger and for affective tone neutral film). For 6 days (D1 to D6), ten healthy volunteers received lorazepam (1 mg bid) or placebo in a randomized cross-over double-blind trial. During each treatment period, emotional induction occurred on D4, D5 and D6. One film excerpt (fear, anger or neutral) was presented each morning after relaxation. Evaluation was performed before and after each emotional induction and included questionnaires (Differential Emotions Scale and physical activation visual analog scales), and neurophysiological parameters (systolic and diastolic blood pressure, heart rate and norepinephrine levels). Globally, the film excerpts induced the predicted emotions. An analysis of variance was undertaken and revealed a significant effect of lorazepam versus placebo. On the Differential Emotions Scale and during fear induction, lorazepam induced a significantly higher increase in fear, anxiety and disgust emotions than placebo, whereas no effect was observed after anger induction. Lorazepam also induced a significantly higher increase in diastolic and systolic blood pressure with no change in heart rate, and physical activation items ("tears" and "faster breathing") without no significant change in norepinephrine. In conclusion, our results are consistent with an overall increase in emotional reactivity with lorazepam (1 mg bid) as compared to placebo. The pertinence of film-induced differentiated emotions has to be confirmed for clinical pharmacological use.     

Impact of smoking cessation on salivary function in healthy volunteers

BACKGROUND: Salivary bicarbonate and epidermal growth factor (EGF) have an important protective role in the oesophagus. The effect of smoking cessation on these aspects of salivary function is unknown. METHODS: Salivary bicarbonate secretion and EGF output were measured before and after attempted smoking cessation in 28 healthy volunteers. Urinary cotinine excretion was used to assess compliance. RESULTS: Negative correlations were found between salivary flow rate and age (rho = -0.34) and between cigarette consumption and salivary flow (rho = -0.27) and salivary bicarbonate concentrations (rho = -0.32). Smoking cessation was associated with a significant increase in salivary bicarbonate secretion (day 0, 1.7 (0.14-6.2); day 7, 3.6 (0.52-6.4); day 21, 3.3 (0.44-6.6) micromol min(-1); P < 0.01) but left salivary EGF output unchanged. CONCLUSION: Smoking cessation is associated with significant improvements in salivary bicarbonate secretion. This would benefit patients with reflux disease who stop smoking.     

Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers

Recent medical publications postulate a connection between the Chronic Fatigue Syndrome (CFS) and disturbed regulation of the circulation, manifesting itself during orthostatic stress testing. Four studies were published on the circulatory response on prolonged head up tilt testing. Numerous CFS patients displayed postural tachycardia or syncope during the test. However, many CFS patients examined had had orthostatic symptoms prior to the examination. It is not certain that cardiovascular dysregulation is present in CFS patients without orthostatic symptoms. It is also not clear whether such a dysregulation would be the effect of physical inactivity or a manifestation of a subtle form of autonomic neuropathy.     

Pharmacodynamic comparison of the acute effects of nomifensine, amphetamine and placebo in healthy volunteers

In a double blind cross over trial the effects of single doses of 100 mg nomifensine, 15 mg racemic amphetamine and placebo were compared in 9 healthy volunteers. Assessments of choice reaction behavior, simple reaction time, critical flicker fusion and attention on continuous calculations were performed together with a series of self rating scales, a side-effect list and vital signs before and 90 min., 180 min. and 360 min. after each administration. While the only significant nomifensine effect was an increase of correct solutions in the continuous calculation task, amphetamine differed from nomifensine and placebor in a number of subjective variables which describe emotional changes typical for drug stimulation. Subjects also expressed the will to have amphetamine prescribed for fatigue and loss of drive, whereas preferences for nomifensine were virtually the same as for placebo. Under amphetamine heart rate and blood pressure were increased and side-effects were frequent. It is concluded that nomifensine showed none of those subjectively pleasant amphetamine effects which are responsible for the reinforcement function leading to amphetamine dependence.